Posttraumatic stress disorder and substance use disorder in adolescent bipolar disorder.

OBJECTIVE: Anxiety disorders such as posttraumatic stress disorder (PTSD) and substance use disorders (SUD) are increasingly recognized as comorbid disorders in children with bipolar disorder (BPD). This study explores the relationship between BPD, PTSD, and SUD in a cohort of BPD and non-BPD adolescents. METHODS: We studied 105 adolescents with BPD and 98 non-mood-disordered adolescent controls. Psychiatric assessments were made using the Kiddie Schedule for Affective Disorders and Schizophrenia-Epidemiologic Version (KSADS-E), or Structured Clinical Interview for DSM-IV (SCID) if 18 years or older. SUD was assessed by KSADS Substance Use module for subjects under 18 years, or SCID module for SUD if age 18 or older. RESULTS: Nine (8%) BPD subjects endorsed PTSD and nine (8%) BPD subjects endorsed subthreshold PTSD compared to one (1%) control subject endorsing full PTSD and two (2%) controls endorsing subthreshold PTSD. Within BPD subjects endorsing PTSD, seven (39%) met criteria for SUD. Significantly more SUD was reported with full PTSD than with subthreshold PTSD (chi(2) = 5.58, p = 0.02) or no PTSD (chi(2) = 6.45, p = 0.01). Within SUD, the order of onset was BPD, PTSD, and SUD in three cases, while in two cases the order was PTSD, BPD, SUD. The remaining two cases experienced coincident onset of BPD and SUD, which then led to trauma, after which they developed PTSD and worsening SUD. CONCLUSION: An increased rate of PTSD was found in adolescents with BPD. Subjects with both PTSD and BPD developed significantly more subsequent SUD, with BPD, PTSD, then SUD being the most common order of onset. Follow-up studies need to be conducted to elucidate the course and causal relationship of BPD, PTSD and SUD.

Cigarette smoking associated with attention deficit hyperactivity disorder.

OBJECTIVE: To evaluate the association between attention deficit hyperactivity disorder (ADHD) and severity of physical dependence on nicotine in a controlled study of adolescents and young adults with ADHD. STUDY DESIGN: In controlled longitudinal family studies of ADHD, we examined self-reports on the modified Fagerström Tolerance Questionnaire (mFTQ) for degrees of physical dependence on nicotine. RESULTS: We obtained mFTQ data from 80 ADHD probands and 86 control probands (mean age, 19.2 years). The smokers with ADHD had significantly higher scores on the mFTQ, indicative of more severe physical dependence on nicotine. Similarly, in current smokers, a positive linear relationship was found between mFTQ score and both inattentive and hyperactive ADHD symptoms. Environmental factors, such as current parental smoking, peer smoking, and living with a smoker, all increased the risk for smoking in those with ADHD compared with controls. CONCLUSION: Male and female smokers with ADHD manifest more severe physical dependence on smoking compared with controls. Important environmental factors appear to add to the risk of smoking associated with ADHD.

Familial transmission of derived phenotypes for molecular genetic studies of substance use disorders.

Although family, twin, and adoption studies indicate that genes play a significant etiologic role in the development of substance use disorders (SUDs), detecting specific genes has been difficult due to uncertainties about how to define SUDs, genetic heterogeneity and variable phenotypic expression of SUD genotypes. We used data from families recruited into six contemporaneous studies of children and adults to derive candidate SUD phenotypes using principle factors factor analysis with varimax rotation. We previously found evidence of two SUD phenotypes in offspring: a psychopathology dimension and a cognitive impairment dimension. We found evidence for one SUD-related phenotype in adults that we term Psychopathology and Cognitive Impairment. Parental factor scores significantly predicted both offspring phenotypes, as well as parental SUD (OR=1.41, p<0.001) and offspring SUD (mother's phenotype: OR=1.34, p=0.04; father's phenotype: OR=1.33, p=0.01). Offspring phenotype predicted offspring SUD (psychopathology phenotype: OR=2.96, p<0.001; cognitive impairment: OR=1.33, p=0.04); in offspring, baseline psychopathology predicted SUD at follow-up assessments (OR=1.55, p=0.01). Results suggest that these candidate SUD phenotypes may be useful for genetic studies of SUD.

Further evidence of an association between adolescent bipolar disorder with smoking and substance use disorders: a controlled study.

Although previous work suggests that juvenile onset bipolar disorder increases risk for substance use disorders and cigarette smoking, the literature on the subject is limited. We evaluated the association of risk for substance use disorders and cigarette smoking with bipolar disorder in adolescents in a case-control study of adolescents with bipolar disorder (n=105, age 13.6+/-2.5 years [mean]; 70% male) and without bipolar disorder ("controls"; n=98, age 13.7+/-2.1 years; 60% male). Rates of substance use and other disorders were assessed with structured interviews (KSADS-E for subjects younger than 18, SCID for 18-year-old subjects). Bipolar disorder was associated with a significant age-adjusted risk for any substance use disorder (hazard ratio[95% confidence interval]=8.68[3.02 25.0], chi(2)=16.06, p<0.001, df=1), alcohol abuse (7.66 [2.20 26.7], chi(2)=10.2, p=0.001, df=1), drug abuse (18.5 [2.46 139.10], chi(2)=8.03, p=0.005, df=1) and dependence (12.1 [1.54 95.50], chi(2)=5.61, p=0.02, df=1), and cigarette smoking (12.3 [2.83 53.69], chi(2)=11.2, p<0.001, df=1), independently of attention deficit/hyperactivity disorder, multiple anxiety, and conduct disorder (CD). The primary predictor of substance use disorders in bipolar youth was older age (BPD-SUD versus BPD+SUD, logistic regression: chi(2)=89.37, p<0.001). Adolescent bipolar disorder is a significant risk factor for substance use disorders and cigarette smoking, independent of psychiatric comorbidity. Clinicians should carefully screen adolescents with bipolar disorder for substance and cigarette use.

Concordance between cigarette smoking and the modified Fagerström Tolerance Questionnaire in controlled studies of ADHD.

Our objective was to compare scores on a smoking questionnaire to a diagnosis of cigarette smoking. As part of follow-ups in studies of ADHD, we assessed for cigarette smoking using structured interviews and the modified Fagerstrom Tolerance Questionnaire (mFTQ). Data were obtained from 162 subjects (mean = 19.2 yrs). ROC analysis and kappa coefficients revealed that a cutoff score of 3 on the mFTQ showed the strongest agreement with a full diagnosis of cigarette smoking (kappa = 0.68). Clinicians and researchers using the mFTQ in adolescents and young adults should consider a cutoff score of 3 to be indicative of cigarette smoking.

Association of bipolar and substance use disorders in parents of adolescents with bipolar disorder.

BACKGROUND: We have previously shown that juvenile bipolar disorder (BPD) is a risk for substance use disorders (SUD). Here we examine the expression of both disorders in families of youth with BPD to evaluate the familial risk mechanism. METHODS: We studied 108 adolescent BPD probands with 187 parents (34 with SUD and 58 parents) and 96 control probands with 177 parents with structured interviews. We compared the prevalence of BPD and SUD with Cox proportional hazards models with time to onset of BPD or SUD as the dependent variable and proband diagnosis (Control, BPD, or BPD+SUD) as the independent variable. RESULTS: The parents of the proband youth with BPD (without SUD) and BPD+SUD were more likely to develop BPD than the parents of control subjects [omnibus test chi2=10.18, p=.006]; we found no differences between the two bipolar groups. Parents of proband youth with BPD and with BPD+SUD were more likely than relatives of control subjects to develop SUD [omnibus test chi2=14.69, p<.001]; however, we found no differences between the parents of the two proband bipolar groups. Within the parents of proband youth with BPD+SUD, we found higher risk of SUD in parents with BPD than in those without BPD [chi2=8.39, p=.004], although the frequency of BPD was low in this group of parents. CONCLUSIONS: Bipolar disorder and SUD are prevalent in the first-degree relatives of adolescents with BPD. Adults with BPD were more likely to manifest SUD with preliminary evidence of BPD and SUD cosegregation.

Deriving phenotypes for molecular genetic studies of substance use disorders: a family study approach.

Although, family, twin, and adoption studies indicate that genes play a significant etiologic role in the development of substance use disorders (SUDs), the specific genes involved have been difficult to detect due, in part, to uncertainties about how best to define SUDs, the possibility of genetic heterogeneity and the variable phenotypic expression of SUD genotypes. The goal of the present work was to determine if phenotypes external to the diagnosis of SUD such as psychopathology and cognitive functioning would show evidence of utility as phenotypes for genetic studies of SUD. We did this by applying factor analysis to multiple measures collected from our family-study program and then determining if these factors were heritable and were co-familial with SUDs. We used data from families recruited into six contemporaneous studies of four psychiatric conditions in children and adults. We found evidence for two SUD related phenotypes. One was an index of Psychopathology and Psychosocial Impairment; the other was an index of school failure and cognitive dysfunction. Both factors showed evidence of heritability, longitudinal stability and familial association with Parental SUD but these findings were stronger for the index of school failure and cognitive dysfunction. Results provide some support for the idea that candidate SUD phenotypes such as psychopathology and cognitive functioning, which are external to the diagnostic criteria for SUDs, may be useful for genetic studies of SUD.

Neuropsychological studies of late onset and subthreshold diagnoses of adult attention-deficit/hyperactivity disorder.

BACKGROUND: Diagnosing attention-deficit/hyperactivity disorder (ADHD) in adults is difficult when the diagnostician cannot establish an onset prior to the DSM-IV criterion of age 7 or if the number of symptoms recalled does not achieve the DSM-IV threshold for diagnosis. Because neuropsychological deficits are associated with ADHD, we addressed the validity of the DSM-IV age at onset and symptom threshold criteria by using neuropsychological test scores as external validators. METHODS: We compared four groups of adults: 1) full ADHD subjects met all DSM-IV criteria for childhood-onset ADHD; 2) late-onset ADHD subjects met all criteria except the age at onset criterion; 3) subthreshold ADHD subjects did not meet full symptom criteria; and 4) non-ADHD subjects did not meet any of the above criteria. RESULTS: Late-onset and full ADHD subjects had similar patterns of neuropsychological dysfunction. By comparison, subthreshold ADHD subjects showed few neuropsychological differences with non-ADHD subjects. CONCLUSIONS: Our results showing similar neuropsychological underpinning in subjects with late-onset ADHD suggest that the DSM-IV age at onset criterion may be too stringent. Our data also suggest that ADHD subjects who failed to ever meet the DSM-IV threshold for diagnosis have a milder form of the disorder.

Diagnosing adult attention deficit hyperactivity disorder: are late onset and subthreshold diagnoses valid?

OBJECTIVE: Diagnosing attention deficit hyperactivity disorder (ADHD) in adults is difficult when diagnosticians cannot establish an onset before the DSM-IV criterion of age 7 or if the number of symptoms recalled does not achieve DSM's diagnosis threshold. METHOD: The authors addressed the validity of DSM-IV's age-at-onset and symptom threshold criteria by comparing four groups of adults: 127 subjects with full ADHD who met all DSM-IV criteria for childhood-onset ADHD, 79 subjects with late-onset ADHD who met all criteria except the age-at-onset criterion, 41 subjects with subthreshold ADHD who did not meet full symptom criteria for ADHD, and 123 subjects without ADHD who did not meet any criteria. The authors hypothesized that subjects with late-onset and subthreshold ADHD would show patterns of psychiatric comorbidity, functional impairment, and familial transmission similar to those seen in subjects with full ADHD. RESULTS: Subjects with late-onset and full ADHD had similar patterns of psychiatric comorbidity, functional impairment, and familial transmission. Most children with late onset of ADHD (83%) were younger than 12. Subthreshold ADHD was milder and showed a different pattern of familial transmission than the other forms of ADHD. CONCLUSIONS: The data about the clinical features of probands and the pattern of transmission of ADHD among relatives found little evidence for the validity of subthreshold ADHD among such subjects, who reported a lifetime history of some symptoms that never met DSM-IV's threshold for diagnosis. In contrast, the results suggested that late-onset adult ADHD is valid and that DSM-IV's age-at-onset criterion is too stringent.

Evolution of male life histories and age-dependent sexual signals under female choice.

Sexual selection theory models evolution of sexual signals and preferences using simple life histories. However, life-history models predict that males benefit from increasing sexual investment approaching old age, producing age-dependent sexual traits. Age-dependent traits require time and energy to grow, and will not fully mature before individuals enter mating competition. Early evolutionary stages pose several problems for these traits. Age-dependent traits suffer from strong viability selection and gain little benefit from mate choice when rare. Few males will grow large traits, and they will rarely encounter choosy females. The evolutionary origins of age-dependent traits therefore remain unclear. I used numerical simulations to analyze evolution of preferences, condition (viability) and traits in an age-structured population. Traits in the model depended on age and condition ("good genes") in a population with no genetic drift. I asked (1) if age-dependent indicator traits and their preferences can originate depending on the strength of selection and the size of the trait; (2) which mode of development (age-dependent versus age-independent) eventually predominates when both modes occur in the population; and (3) if age-independent traits can invade a population with age-dependent traits. Age-dependent traits evolve under weaker selection and at smaller sizes than age-independent traits. This result held in isolation and when the types co-occur. Evolution of age-independent traits depends only on trait size, whereas evolution of age-dependent traits depends on both strength of selection and growth rate. Invasion of age-independence into populations with established traits followed a similar pattern with age-dependence predominating at small trait sizes. I suggest that reduced adult mortality facilitates sexual selection by favoring the evolution of age-dependent sexual signals under weak selection.

Association between attention-deficit/hyperactivity disorder and sleep impairment in adulthood: evidence from a large controlled study.

OBJECTIVE: To examine whether sleep impairment is associated with attention-deficit/hyperactivity disorder (ADHD) in adults. METHOD: In a study conducted from 1998 to 2003, we identified sleep characteristics in a community sample of 182 cases of DSM-IV ADHD or ADHD not otherwise specified and 117 non-ADHD controls aged 18 to 55 years. Attention-deficit/hyperactivity disorder status, current and lifetime psychiatric comorbidity, and pharmacologic treatment of ADHD were identified with the Structured Clinical Interview for DSM-IV and with modules from the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic Version. Sleep problems were characterized by self-report. We separately accounted for the contribution of age at ADHD onset, ADHD pharmacotherapy, lifetime bipolar disorder, and the following lifetime and current comorbidities: depression, generalized anxiety, substance abuse, and multiple anxiety disorders. RESULTS: Adults with ADHD went to bed later than control subjects and had a wider range of bedtimes (mean +/- SD = 18 +/- 92 min vs 54 +/- 69 min before midnight; P < .001), were more likely to take over an hour to fall asleep (OR = 5.22, P = .001), and were more likely (P < .003) to experience difficulty going to bed, going to sleep, sleeping restfully, or waking in the morning. Adults with ADHD experienced daytime sleepiness more often (OR = 2.23, P = .003) and reported more sleep problems (mean +/- SD = 6.7 +/- 2.5 vs 4.3 +/- 2.2; P < .001) than controls. All sleep impairments were significantly associated with ADHD independent of contributions to sleep disruption from ADHD pharmacotherapy, comorbidities likely to contribute to sleep disturbance, and age at ADHD onset. CONCLUSION: Sleep disturbances that are not attributable to comorbid mental health conditions or ADHD pharmacotherapy are associated with ADHD in adulthood. Clinicians and researchers should consider the potential contribution of sleep disruption to the clinical presentation of adults with ADHD.

Effect of prior stimulant treatment for attention-deficit/hyperactivity disorder on subsequent risk for cigarette smoking and alcohol and drug use disorders in adolescents.

OBJECTIVE: To examine the effects of early stimulant treatment on subsequent risk for cigarette smoking and substance use disorders (SUDs) in adolescents with attention-deficit/hyperactivity disorder (ADHD). DESIGN: Case-controlled, prospective, 5-year follow-up study. SETTING: Massachusetts General Hospital, Boston. PARTICIPANTS: Adolescents with and without ADHD from psychiatric and pediatric sources. Blinded interviewers determined all diagnoses using structured interviews. Intervention Naturalistic treatment exposure with psychostimulants for ADHD. MAIN OUTCOME MEASURES: We modeled time to onset of SUDs and smoking as a function of stimulant treatment. RESULTS: We ascertained 114 subjects with ADHD (mean age at follow-up, 16.2 years) having complete medication and SUD data; 94 of the subjects were treated with stimulants. There were no differences in SUD risk factors between naturalistically treated and untreated groups other than family history of ADHD. We found no increased risks for cigarette smoking or SUDs associated with stimulant therapy. We found significant protective effects of stimulant treatment on the development of any SUD (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.13-0.60; chi(2)(113) = 10.57, P = .001) and cigarette smoking (HR, 0.28; 95% CI, 0.14-0.60; chi(2)(111) = 10.05, P = .001) that were maintained when controlling for conduct disorder. We found no effects of time to onset or duration of stimulant therapy on subsequent SUDs or cigarette smoking in subjects with ADHD. CONCLUSION: Stimulant therapy does not increase but rather reduces the risk for cigarette smoking and SUDs in adolescents with ADHD.

A naturalistic study of the effects of pharmacotherapy on substance use disorders among ADHD adults.

BACKGROUND: Studies of adults with attention deficit hyperactivity disorder (ADHD) show an elevated prevalence of substance use disorders (SUDs) and the substance abuse literature shows that ADHD is elevated in substance users. Some researchers postulate that stimulant treatment of ADHD increases the risk for SUD in ADHD patients but follow-up studies suggest treatment protects patients from subsequent SUDs. This report uses retrospective data to assess the impact of prior ADHD pharmacotherapy on SUDs in 206 ADHD adults (n=79 late-onset ADHD, n=127 full ADHD) grouped by lifetime history of ADHD treatment (no treatment, past treatment, current and past treatment). METHOD: Structured Clinical Interview for DSM-IV (SCID) data were used to establish abuse and dependence, and Drug Use Screening Inventory (DUSI) responses were used to establish prevalence of use, preference for cigarettes, alcohol and drugs of abuse, complications from use, and motivation for use (get high, change mood, sleep better). RESULTS: No differences were found in the prevalence of cigarette smoking, alcohol or drug abuse or dependence, as well as no significant differences in 1-month prevalence of any use or use more than 20 times. No differences were found in complications of drug or alcohol use across groups. Subjects with current treatment rated getting high as a motivating factor significantly more frequently than subjects in the past treatment group; this result lost significance when we included ADHD diagnostic category. CONCLUSIONS: Our results are consistent across substances and ADHD diagnoses, and support the hypothesis that pharmacotherapy does not cause subsequent SUDs.

Do individuals with ADHD self-medicate with cigarettes and substances of abuse? Results from a controlled family study of ADHD.

Studies report increased rates of cigarette and substance use in youths with Attention-Deficit/Hyperactivity Disorder (ADHD), though the mechanism of risk remains unclear. The present study tests the hypothesis that ADHD individuals "self-medicate" with cigarettes and substances of abuse. As part of five- and ten-year case-control longitudinal family studies of ADHD, responses to the Drug Use Screening Inventory (DUSI) were examined for evidence of self-medication. DUSI data from 90 ADHD probands and 96 control probands were obtained. Thirty-six percent of subjects reported self-medication, 25% used to get high, and 39% had unknown motivation. No significant differences were found between ADHD and controls in motivation. ADHD symptoms did not differ between self-medicators and subjects using to get high. DUSI problem scores were higher in ADHD (versus controls), those using to get high (versus self-medicators), and subjects using alcohol (versus other substances). More than one-third of adolescents and young adults endorsed using cigarettes and substances for self medication. Studies clarifying the role of self-medication in substance use disorders are necessary.