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.

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.

Family history of depression is associated with younger age of onset in patients with recurrent depression.

BACKGROUND: Genetic epidemiology data suggest that younger age of onset is associated with family history (FH) of depression. The present study tested whether the presence of FH for depression or anxiety in first-degree relatives determines younger age of onset for depression. METHOD: A sample of 1022 cases with recurrent major depressive disorder (MDD) was recruited at the Max Planck Institute and at two affiliated hospitals. Patients were assessed using the Schedules for Clinical Assessment in Neuropsychiatry and questionnaires including demographics, medical history, questions on the use of alcohol and tobacco, personality traits and life events. Survival analysis and the Cox proportional hazard model were used to determine whether FH of depression signals earlier age of onset of depression. RESULTS: Patients who reported positive FH had a significantly earlier age of onset than patients who did not report FH of depression (log-rank=48, df=1, p<0.0001). The magnitude of association of FH varies by age of onset, with the largest estimate for MDD onset before age 20 years (hazard ratio=2.2, p=0.0009), whereas FH is not associated with MDD for onset after age 50 years (hazard ratio=0.89, p=0.5). The presence of feelings of guilt, anxiety symptoms and functional impairment due to depressive symptoms appear to characterize individuals with positive FH of depression. CONCLUSIONS: FH of depression contributes to the onset of depression at a younger age and may affect the clinical features of the illness.

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.

Epidemiology of multiple childhood traumatic events: child abuse, parental psychopathology, and other family-level stressors.

BACKGROUND: Multiple family-level childhood stressors are common and are correlated. It is unknown if clusters of commonly co-occurring stressors are identifiable. The study was designed to explore family-level stressor clustering in the general population, to estimate the prevalence of exposure classes, and to examine the correlation of sociodemographic characteristics with class prevalence. METHOD: Data were collected from an epidemiological sample and analyzed using latent class regression. RESULTS: A six-class solution was identified. Classes were characterized by low risk (prevalence=23%), universal high risk (7 %), family conflict (11 %), household substance problems (22 %), non-nuclear family structure (24 %), parent's mental illness (13 %). CONCLUSIONS: Class prevalence varied with race and welfare status, not gender. Interventions for childhood stressors are person-focused; the analytic approach may uniquely inform resource allocation.

Stability and change in children's intelligence quotient scores: a comparison of two socioeconomically disparate communities.

The authors estimated the influence of familial factors and community disadvantage on changes in children's intelligence quotient (IQ) scores from age 6 years to age 11 years. Data were obtained from a longitudinal study of the neuropsychiatric sequelae of low birth weight in two socioeconomically disparate, geographically defined communities in the Detroit, Michigan, metropolitan area. Representative samples of low birth weight and normal birth weight children from the City of Detroit (urban) and nearby middle-class suburbs (suburban) were assessed at age 6 years (in 1990-1992) and age 11 years (in 1995-1997) (n = 717). Children's IQs were measured using the Wechsler Intelligence Scale for Children-Revised. The familial factors considered included maternal IQ, education, and marital status. Multiple regression analysis applying generalized estimating equations was used. The IQs of urban children, regardless of birth weight, declined from age 6 years to age 11 years. The downward shift increased by 50% the proportion of urban children scoring 1 standard deviation below the standardized IQ mean of 100. A negligible change was observed in suburban children. Maternal IQ, education, and marital status and low birth weight predicted IQ at age 6 years but were unrelated to IQ change. Growing up in a racially segregated and disadvantaged community, more than individual and familial factors, may contribute to a decline in IQ score in the early school years.

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.

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).

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.

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.

Vulnerability to assaultive violence: further specification of the sex difference in post-traumatic stress disorder.

BACKGROUND: We examine potential sources of the sex differences in post-traumatic stress disorder (PTSD) in the community. METHODS: Data were obtained from a representative sample of 2181 persons aged 18-45 years in the Detroit primary metropolitan statistical area, which is a six-county area containing more than four million residents. A random digit dialling method was used to select the sample and a computer-assisted telephone interview was used to obtain the data. DSM-IV PTSD was assessed with respect to a randomly selected trauma from the list of qualifying traumas reported by each respondent. RESULTS: The lifetime prevalence of exposure and the mean number of traumas were lower in females than males. The overall conditional risk of PTSD (i.e. the probability of PTSD among those exposed to a trauma) was approximately twofold higher in females than males, adjusting for the sex difference in the distribution of trauma types. The sex difference was due primarily to females' greater risk following assaultive violence. The sex difference in the avoidance and numbing symptom group following assaultive violence exceeded the sex differences in other symptom groups. CONCLUSIONS: Future research should focus on sex differences in the response to assaultive violence, including potential explanations for females' greater probability to experience avoidance and numbing.

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.

Investigations of causal pathways between PTSD and drug use disorders.

Although numerous studies have demonstrated an association between PTSD and substance use disorders, little is known about the causal nature of this relationship. In this article, we put forth and test major causal hypotheses. Specific hypotheses to be tested include self-medication of PTSD symptoms, substance users' high risk of exposure to traumatic events, and drug users' increased susceptibility to PTSD following a traumatic exposure. We also examine the possibility of an indirect pathway linking drug use disorders and PTSD via a shared vulnerability. Evidence for these causal hypotheses is evaluated using Hill's criteria for causal inference: strength, consistency, specificity, temporality, gradient, plausibility, coherence, experimental evidence, and analogy. We present data analytic strategies that exploit information about the temporal order of PTSD and drug use disorders to shed light on their causal relationship. Finally, we present findings on the PTSD/drug use disorder association from an epidemiologic study of young adults.

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.

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.

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.

Anxiety disorders and the emergence of sex differences in major depression.

OBJECTIVE: To examine the role of anxiety disorders in the development of sex differences in the risk of major depression. DESIGN: An epidemiologic study. PATIENTS: This study surveyed 1007 young adults, randomly selected from a large HMO in southeastern Michigan. METHOD: The National Institute of Mental Health's Diagnostic Interview Schedule was administered to measure major depression and specific anxiety disorders (as per Diagnostic and Statistical Manual of Mental Disorders, third edition revised, guidelines). A composite variable--"any anxiety"--was used, and age of onset was defined as the age at which the earliest anxiety disorder began. RESULTS: Prior anxiety signaled an increased risk for major depression in both sexes. Women were not more vulnerable than men to becoming depressed after an anxiety disorder. Prior anxiety disorders accounted for a considerable part of the sex differences in major depression. Controlling for prior substance use disorder did not alter the results. CONCLUSION: Women's higher rates of anxiety disorders might play a role in their higher risk of depression. Substance use disorder is not men's counterpart of anxiety in terms of its potential role in the onset of depression. Future research should address the question of women's greater risk for anxiety disorders. Intervention trials to examine whether effective treatments of anxiety disorders might reduce the risk of depression would shed light on the mechanisms that link anxiety and depression.

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.

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.