Patrick D. Quinn

Associations of Maternal Antidepressant Use During the First Trimester of Pregnancy With Preterm Birth, Small for Gestational Age, Autism Spectrum Disorder, and Attention-Deficit/Hyperactivity Disorder in Offspring

Importance Prenatal antidepressant exposure has been associated with adverse outcomes. Previous studies, however, may not have adequately accounted for confounding. Objective To evaluate alternative hypotheses for associations between first-trimester antidepressant exposure and birth and neurodevelopmental problems. Design, Setting, and Participants This retrospective cohort study included Swedish offspring born between 1996 and 2012 and followed up through 2013 or censored by death or emigration. Analyses controlling for pregnancy, maternal and paternal covariates, as well as sibling comparisons, timing of exposure comparisons, and paternal comparisons, were used to examine the associations. Exposures Maternal self-reported first-trimester antidepressant use and first-trimester antidepressant dispensations. Main Outcomes and Measures Preterm birth (<37 gestational weeks), small for gestational age (birth weight <2 SDs below the mean for gestational age), and first inpatient or outpatient clinical diagnosis of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring. Results Among 1 580 629 offspring (mean gestational age, 279 days; 48.6% female; 1.4% [n = 22 544] with maternal first-trimester self-reported antidepressant use) born to 943 776 mothers (mean age at childbirth, 30 years), 6.98% of exposed vs 4.78% of unexposed offspring were preterm, 2.54% of exposed vs 2.19% of unexposed were small for gestational age, 5.28% of exposed vs 2.14% of unexposed were diagnosed with autism spectrum disorder by age 15 years, and 12.63% of exposed vs 5.46% of unexposed were diagnosed with attention-deficit/hyperactivity disorder by age 15 years. At the population level, first-trimester exposure was associated with all outcomes compared with unexposed offspring (preterm birth odds ratio [OR], 1.47 [95% CI, 1.40-1.55]; small for gestational age OR, 1.15 [95% CI, 1.06-1.25]; autism spectrum disorder hazard ratio [HR], 2.02 [95% CI, 1.80-2.26]; attention-deficit/hyperactivity disorder HR, 2.21 [95% CI, 2.04-2.39]). However, in models that compared siblings while adjusting for pregnancy, maternal, and paternal traits, first-trimester antidepressant exposure was associated with preterm birth (OR, 1.34 [95% CI, 1.18-1.52]) but not with small for gestational age (OR, 1.01 [95% CI, 0.81-1.25]), autism spectrum disorder (HR, 0.83 [95% CI, 0.62-1.13]), or attention-deficit/hyperactivity disorder (HR, 0.99 [95% CI, 0.79-1.25]). Results from analyses assessing associations with maternal dispensations before pregnancy and with paternal first-trimester dispensations were consistent with findings from the sibling comparisons. Conclusions and Relevance Among offspring born in Sweden, after accounting for confounding factors, first-trimester exposure to antidepressants, compared with no exposure, was associated with a small increased risk of preterm birth but no increased risk of small for gestational age, autism spectrum disorder, or attention-deficit/hyperactivity disorder.

Incident and long-term opioid therapy among patients with psychiatric conditions and medications: A national study of commercial health care claims

Abstract There is growing evidence that opioid prescribing in the United States follows a pattern in which patients who are at the highest risk of adverse outcomes from opioids are more likely to receive long-term opioid therapy. These patients include, in particular, those with substance use disorders (SUDs) and other psychiatric conditions. This study examined health insurance claims among 10,311,961 patients who filled prescriptions for opioids. Specifically, we evaluated how opioid receipt differed among patients with and without a wide range of preexisting psychiatric and behavioral conditions (ie, opioid and nonopioid SUDs, suicide attempts or other self-injury, motor vehicle crashes, and depressive, anxiety, and sleep disorders) and psychoactive medications (ie, antidepressants, benzodiazepines, hypnotics, mood stabilizers, antipsychotics, and medications used for SUD, tobacco cessation, and attention-deficit/hyperactivity disorder). Relative to those without, patients with all assessed psychiatric conditions and medications had modestly greater odds of subsequently filling prescriptions for opioids and, in particular, substantially greater risk of long-term opioid receipt. Increases in risk for long-term opioid receipt in adjusted Cox regressions ranged from approximately 1.5-fold for prior attention-deficit/hyperactivity disorder medication prescriptions (hazard ratio [HR] = 1.53; 95% confidence interval [CI], 1.48-1.58) to approximately 3-fold for prior nonopioid SUD diagnoses (HR = 3.15; 95% CI, 3.06-3.24) and nearly 9-fold for prior opioid use disorder diagnoses (HR = 8.70; 95% CI, 8.20-9.24). In sum, we found evidence of greater opioid receipt among commercially insured patients with a breadth of psychiatric conditions. Future studies assessing behavioral outcomes associated with opioid prescribing should consider preexisting psychiatric conditions.

Association Between Medication Use for Attention-Deficit/Hyperactivity Disorder and Risk of Motor Vehicle Crashes

Importance Motor vehicle crashes (MVCs) are a major public health problem. Research has demonstrated that individuals with attention-deficit/hyperactivity disorder (ADHD) are more likely to experience MVCs, but the effect of ADHD medication treatment on the risk of MVCs remains unclear. Objective To explore associations between ADHD medication use and risk of MVCs in a large cohort of patients with ADHD. Design, Setting, and Participants For this study, a US national cohort of patients with ADHD (n = 2 319 450) was identified from commercial health insurance claims between January 1, 2005, and December 31, 2014, and followed up for emergency department visits for MVCs. The study used within-individual analyses to compare the risk of MVCs during months in which patients received ADHD medication with the risk of MVCs during months in which they did not receive ADHD medication. Exposures Dispensed prescription of ADHD medications. Main Outcomes and Measures Emergency department visits for MVCs. Results Among 2 319 450 patients identified with ADHD, the mean (SD) age was 32.5 (12.8) years, and 51.7% were female. In the within-individual analyses, male patients with ADHD had a 38% (odds ratio, 0.62; 95% CI, 0.56-0.67) lower risk of MVCs in months when receiving ADHD medication compared with months when not receiving medication, and female patients had a 42% (odds ratio, 0.58; 95% CI, 0.53-0.62) lower risk of MVCs in months when receiving ADHD medication. Similar reductions were found across all age groups, across multiple sensitivity analyses, and when considering the long-term association between ADHD medication use and MVCs. Estimates of the population-attributable fraction suggested that up to 22.1% of the MVCs in patients with ADHD could have been avoided if they had received medication during the entire follow-up. Conclusions and Relevance Among patients with ADHD, rates of MVCs were lower during periods when they received ADHD medication. Considering the high prevalence of ADHD and its association with MVCs, these findings warrant attention to this prevalent and preventable cause of mortality and morbidity.

Medication for Attention-Deficit/Hyperactivity Disorder and Risk for Depression: A Nationwide Longitudinal Cohort Study

BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is associated with high rates of psychiatric comorbidity, including depression. However, it is unclear whether ADHD medication increases or decreases the risk for depression. METHODS We studied all individuals with a diagnosis of ADHD born between 1960 and 1998 in Sweden (N = 38,752). We obtained data for prescription of ADHD medication, diagnosis of depression and other psychiatric disorders, and sociodemographic factors from population-based registers. The association between ADHD medication and depression was estimated with Cox proportional hazards regression. RESULTS After adjustment for sociodemographic and clinical confounders, ADHD medication was associated with a reduced long-term risk (i.e., 3 years later) for depression (hazard ratio = 0.58; 95% confidence interval, 0.51-0.67). The risk was lower for longer duration of ADHD medication. Also, ADHD medication was associated with reduced rates of concurrent depression; within-individual analysis suggested that occurrence of depression was 20% less common during periods when patients received ADHD medication compared with periods when they did not (hazard ratio = 0.80; 95% confidence interval, 0.70-0.92). CONCLUSIONS Our study suggests that ADHD medication does not increase the risk of later depression; rather, medication was associated with a reduced risk for subsequent and concurrent depression.

Association Between Maternal Smoking During Pregnancy and Severe Mental Illness in Offspring

Importance Several recent population-based studies have linked exposure to maternal smoking during pregnancy to increased risk of severe mental illness in offspring (eg, bipolar disorder, schizophrenia). It is not yet clear, however, whether this association results from causal teratogenic effects or from confounding influences shared by smoking and severe mental illness. Objective To examine the association between smoking during pregnancy and severe mental illness in offspring, adjusting for measured covariates and unmeasured confounding using family-based designs. Design, Setting, and Participants This study analyzed population register data through December 31, 2013, for a cohort of 1 680 219 individuals born in Sweden from January 1, 1983, to December 31, 2001. Associations between smoking during pregnancy and severe mental illness in offspring were estimated with adjustment for measured covariates. Cousins and siblings who were discordant on smoking during pregnancy and severe mental illness were then compared, which helped to account for unmeasured genetic and environmental confounding by design. Exposures Maternal self-reported smoking during pregnancy, obtained from antenatal visits. Main Outcomes and Measures Severe mental illness, with clinical diagnosis obtained from inpatient and outpatient visits and defined using International Classification of Diseases codes for bipolar disorder and schizophrenia spectrum disorders. Results Of the 1 680 219 offspring included in the analysis, 816 775 (48.61%) were female. At the population level, offspring exposed to moderate and high levels of smoking during pregnancy had greater severe mental illness rates than did unexposed offspring (moderate smoking during pregnancy: hazard ratio [HR], 1.25; 95% CI, 1.19-1.30; high smoking during pregnancy: HR, 1.51; 95% CI, 1.44-1.59). These associations decreased in strength with increasing statistical and methodologic controls for familial confounding. In sibling comparisons with within-family covariates, associations were substantially weaker and nonsignificant (moderate smoking during pregnancy: HR, 1.09; 95% CI, 0.94-1.26; high smoking during pregnancy: HR, 1.14; 95% CI, 0.96-1.35). The pattern of associations was consistent across subsets of severe mental illness disorders and was supported by further sensitivity analyses. Conclusions and Relevance This population- and family-based study failed to find support for a causal effect of smoking during pregnancy on risk of severe mental illness in offspring. Rather, these results suggest that much of the observed population-level association can be explained by measured and unmeasured factors shared by siblings.

ADHD Medication and Substance-Related Problems

OBJECTIVE Substance use disorders are major contributors to excess mortality among individuals with attention deficit hyperactivity disorder (ADHD), yet associations between pharmacological ADHD treatment and substance-related problems remain unclear. This study investigated concurrent and long-term associations between ADHD medication treatment and substance-related events. METHOD The authors analyzed 2005-2014 commercial health care claims from 2,993,887 (47.2% female) adolescent and adult ADHD patients. Within-individual analyses compared the risk of substance-related events (i.e., emergency department visits related to substance use disorders) during months in which patients received prescribed stimulant medication or atomoxetine relative to the risk during months in which they did not. RESULTS In adjusted within-individual comparisons, relative to periods in which patients did not receive ADHD medication, male patients had 35% lower odds of concurrent substance-related events when receiving medication (odds ratio=0.65, 95% CI=0.64-0.67), and female patients had 31% lower odds of concurrent substance-related events (odds ratio=0.69, 95% CI=0.67-0.71). Moreover, male patients had 19% lower odds of substance-related events 2 years after medication periods (odds ratio=0.81, 95% CI=0.78-0.85), and female patients had 14% lower odds of substance-related events 2 years after medication periods (odds ratio=0.86, 95% CI= 0.82-0.91). Sensitivity analyses supported most findings but were less consistent for long-term associations among women. CONCLUSIONS These results provide evidence that receiving ADHD medication is unlikely to be associated with greater risk of substance-related problems in adolescence or adulthood. Rather, medication was associated with lower concurrent risk of substance-related events and, at least among men, lower long-term risk of future substance-related events.

Childhood attention-deficit/hyperactivity disorder symptoms and the development of adolescent alcohol problems: A prospective, population-based study of Swedish twins

Children with attention‐deficit/hyperactivity disorder (ADHD) are at increased risk of problematic alcohol and other substance use in adolescence. This study used data from an ongoing, prospective, population‐based twin study of Swedish children and adolescents to evaluate the extent to which the association between ADHD symptoms and alcohol problems reflects a unique source of genetic or environmental risk related to ADHD versus a broader predisposition to youth externalizing behavior. We used all available data from same‐sex monozygotic (MZ) and dizygotic (DZ) twins on ADHD symptoms in childhood (age 9/12; N = 15,549) and alcohol problems in late adolescence (age 18; N = 2,564). Consistent with prior longitudinal studies, the phenotypic association between hyperactive/impulsive ADHD symptoms and alcohol problems was small in magnitude, whereas the association for inattentive symptoms was even weaker. Additive genetic influences explained 99.8% of the association between hyperactive/impulsive symptoms and alcohol problems. Furthermore, we found that the genetic risk specifically associated with hyperactive/impulsive symptoms was attenuated when estimated in the context of externalizing behavior liability during childhood, of which ADHD symptoms were specific expressions. In sensitivity analyses exploring hyperactivity in mid‐adolescence, we found a similar pattern of genetic associations. These results are consistent with previous findings of genetically driven overlap in the etiology of ADHD and problematic alcohol use. At least some of this co‐occurrence may result from a general predisposition to externalizing behaviors in youth.

Association of Mental Health Conditions and Treatments With Long-term Opioid Analgesic Receipt Among Adolescents

Importance Adults with mental health conditions are more likely than those without to receive long-term opioid therapy. Less is known about opioid therapy among adolescents, especially those with mental health conditions. Objective To examine associations between preexisting mental health conditions and treatments and initiation of any opioid and long-term opioid therapy among adolescents. Design, Setting, and Participants A cohort of 1 224 520 incident opioid recipients without cancer diagnoses aged 14 to 18 years at first receipt was extracted from nationwide commercial health care claims data from January 1, 2003, to December 31, 2014. Analysis was conducted from August 19, 2016, to November 16, 2017. Associations between preexisting mental health conditions and treatments and any opioid receipt were examined by comparing recipients with nonrecipients matched on sex, calendar year and years of age of first enrollment, and months of enrollment (prior to the index month for recipients, ever for nonrecipients). Associations between preexisting mental health conditions and treatments and subsequent long-term opioid therapy were examined among recipients with at least 6 months’ follow-up using Cox proportional hazards regressions adjusted for demographics. Exposures Mental health condition diagnoses and treatments recorded in inpatient, outpatient, and filled-prescription claims prior to opioid receipt. Main Outcomes and Measures Opioid receipt, defined as any opioid analgesic prescription claim, and long-term opioid therapy, defined as more than 90 days’ supply within a 6-month window having no gaps in supply of more than 32 days. Results Of the 1 224 520 new opioid recipients included, the median age at first receipt was 17 years (interquartile range, 16-18 years), and 51.1% were female. Median follow-up after first receipt was 625 days (interquartile range, 255-1268 days). Adolescents with anxiety, mood, neurodevelopmental, sleep, and nonopioid substance use disorders and most mental health treatments were significantly more likely to receive any opioid (odds ratios from 1.13 [95% CI, 1.10-1.16] for nonopioid substance use disorders to 1.69 [95% CI, 1.58-1.81] for nonbenzodiazepine hypnotics). Among the 1 000 453 opioid recipients (81.7%) who had at least 6 months’ follow-up, the cumulative incidence of long-term opioid therapy was 3.0 (95% CI, 2.8-3.1) per 1000 recipients within 3 years after first opioid receipt. All preexisting mental health conditions and treatments were strongly associated with higher rates of long-term opioid therapy (adjusted hazard ratios from 1.73 [95% CI 1.54-1.95] for attention-deficit/hyperactivity disorder to 8.90 [95% CI, 5.85-13.54] for opioid use disorder). Conclusions and Relevance Commercially insured adolescents with many types of preexisting mental health conditions and treatments were modestly more likely to receive any opioid and were substantially more likely to subsequently transition to long-term opioid therapy relative to those without, although overall rates of long-term opioid therapy were low.

447) Psychiatric predictors of receiving prescription opioids in two national samples

Morphine was the first introduced in the 19th century as a potent opiate analgesic. Since then, it has become the de facto standard to which all opioids are compared. While this has led to useful conversion ratios between opioids, the Morphine Equivalent Dose (MED) has significant limitations. Herein, we describe examples of analgesics that challenge the usefulness of the MEDand propose alternative nomenclature. By nature of its derivation, MED refers specifically to the mu-agonist portion of any analgesic. This is useful when dealing with classical opioids as one can estimate the relative mu-mediated analgesia and adverse effects – most notably respiratory depression. Where the MED ratio falls short is with ‘‘atypical’’ opioids or those with multiple mechanisms. Examples of these include buprenorphine, tramadol and tapentadol. In the case of tapentadol, analgesic efficacy is thought to be derived from a combination of mu-agonism and norepinephrine reuptake inhibition. Thus, while the MED ratio most often cited is 0.4, this does not take into account the portion of its efficacy that is derived from a non-mu mechanism. In fact, in preclinical models tapentadol is 18x less potent at the mu opioid receptor than morphine. Tramadol is similarly thought to have multiple mechanisms: weak mu agonism and both serotonin and norepinephrine reuptake inhibition, all of which contribute to its analgesia and complicate its conversion. Buprenorphine is thought to be a partial, but tightly bound agonist at themu receptor. As a result, it exhibits a unique ceiling effect of efficacy and adverse events. Thus, anyMED conversion speaks only to analgesia and not necessarily safety. In light of the unique properties of the examples above, itmay bemore appropriate to utilize equianalgesic ratios when speaking of efficacy and relative mu contribution when discussing safety, rather than attempting to capture both aspects with MED.

Attention-deficit/hyperactivity disorder medication and seizures

Objective Individuals with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of seizures, but there is uncertainty about whether ADHD medication treatment increases risk among patients with and without preexisting seizures. Methods We followed a sample of 801,838 patients with ADHD who had prescribed drug claims from the Truven Health MarketScan Commercial Claims and Encounters databases to examine whether ADHD medication increases the likelihood of seizures among ADHD patients with and without a history of seizures. First, we assessed overall risk of seizures among patients with ADHD. Second, within-individual concurrent analyses assessed odds of seizure events during months when a patient with ADHD received ADHD medication compared with when the same individual did not, while adjusting for antiepileptic medications. Third, within-individual long-term analyses examined odds of seizure events in relation to the duration of months over the previous 2 years patients received medication. Results Patients with ADHD were at higher odds for any seizure compared with non-ADHD controls (odds ratio [OR] = 2.33, 95% confidence interval [CI] = 2.24–2.42 males; OR = 2.31, 95% CI = 2.22–2.42 females). In adjusted within-individual comparisons, ADHD medication was associated with lower odds of seizures among patients with (OR = 0.71, 95% CI = 0.60–0.85) and without (OR = 0.71, 95% CI = 0.62–0.82) prior seizures. Long-term within-individual comparisons suggested no evidence of an association between medication use and seizures among individuals with (OR = 0.87, 95% CI = 0.59–1.30) and without (OR = 1.01, 95% CI = 0.80–1.28) a seizure history. Conclusions Results reaffirm that patients with ADHD are at higher risk of seizures. However, ADHD medication was associated with lower risk of seizures within individuals while they were dispensed medication, which is not consistent with the hypothesis that ADHD medication increases risk of seizures.