Multiple lines of evidence point to glutamatergic signaling in the postsynaptic density (PSD) as ... more Multiple lines of evidence point to glutamatergic signaling in the postsynaptic density (PSD) as a pathophysiologic mechanism in schizophrenia. Integral to PSD glutamatergic signaling is reciprocal interplay between GluN and mGluR5 signaling. We examined agonist-induced mGluR5 signaling in the postmortem dorsolateral prefrontal cortex (DLPFC) derived from 17 patients and age-matched and sex-matched controls. The patient group showed a striking reduction in mGluR5 signaling, manifested by decreases in Gq/11 coupling and association with PI3K and Homer compared to controls (p < 0.01 for all). This was accompanied by increases in serine and tyrosine phosphorylation of mGluR5, which can decrease mGluR5 activity via desensitization (p < 0.01). In addition, we find altered protein-protein interaction (PPI) of mGluR5 with RGS4, norbin, Preso 1 and tamalin, which can also attenuate mGluR5 activity. We previously reported molecular underpinnings of GluN hypofunction (decreased GluN2 ph...
Warfarin and antihyperlipidemics are commonly co-prescribed. Some antihyperlipidemics may inhibit... more Warfarin and antihyperlipidemics are commonly co-prescribed. Some antihyperlipidemics may inhibit warfarin deactivation via the hepatic cytochrome P450 system. Therefore, antihyperlipidemic discontinuation has been hypothesized to result in underanticoagulation, as warfarin metabolism is no longer inhibited. We quantified the risk of venous thromboembolism (VTE) and ischemic stroke (IS) due to statin and fibrate discontinuation in warfarin users, in which warfarin was initially dose-titrated during ongoing antihyperlipidemic therapy. Using 1999-2011 United States Medicaid claims among 69 million beneficiaries, we conducted a set of bidirectional self-controlled case series studies-one for each antihyperlipidemic. Outcomes were hospital admissions for VTE/IS. The risk segment was a maximum of 90 days immediately following antihyperlipidemic discontinuation, the exposure of interest. Time-varying confounders were included in conditional Poisson models. We identified 629 study eligible...
To examine the association between individual antidiabetic sulfonylureas and outpatient-originati... more To examine the association between individual antidiabetic sulfonylureas and outpatient-originating sudden cardiac arrest and ventricular arrhythmia (SCA/VA). We conducted a retrospective cohort study using 1999-2010 U.S. Medicaid claims from five large states. Exposures were determined by incident use of glyburide, glimepiride, or glipizide. Glipizide served as the reference exposure, as its effects are believed to be highly pancreas specific. Outcomes were ascertained by a validated ICD-9-based algorithm indicative of SCA/VA (positive predictive value ∼85%). Potential confounding was addressed by adjustment for multinomial high-dimensional propensity scores included as continuous variables in a Cox proportional hazards model. Of sulfonylurea users under study ( = 519,272), 60.3% were female and 34.9% non-Hispanic Caucasian, and the median age was 58.0 years. In 176,889 person-years of sulfonylurea exposure, we identified 632 SCA/VA events (50.5% were immediately fatal) for a crude...
To examine the comparative safety of individual NSAIDs when given concomitantly with clopidogrel.... more To examine the comparative safety of individual NSAIDs when given concomitantly with clopidogrel. We conducted a retrospective cohort study using Medicaid claims from five US states during 1999-2010, supplemented with Medicare claims for dual-enrollees. The exposure of interest was the first concomitant use of clopidogrel and one of the 10 selected NSAIDs after a 1-year baseline period. The outcomes were: all-cause mortality; acute myocardial infarction (AMI)/ischemic stroke; and gastrointestinal bleeding (GIB)/intracranial hemorrhage (ICH). We calculated the hazard ratio of each NSAID for each outcome, with ibuprofen as the reference drug, using high-dimensional propensity score-adjusted proportional-hazards regression models. Of 1,060,412 clopidogrel users, 268,114 concomitant NSAID users met inclusion/exclusion criteria, contributing 48,483 person-years. We observed 2,463 deaths, 2,822 AMI/ischemic stroke outcomes, and 2,620 GIB/ICH outcomes, for unadjusted incidence rates of 50....
Background: Administrative claims of United States Centers for Medicare and Medicaid Services (CM... more Background: Administrative claims of United States Centers for Medicare and Medicaid Services (CMS) beneficiaries have long been used in non-experimental research. While CMS performs in-house checks of these claims, little is known of their quality for conducting pharmacoepidemiologic research. We performed exploratory analyses of the quality of Medicaid and Medicare data obtained from CMS and its contractors. Methods: Our study population consisted of Medicaid beneficiaries (with and without dual coverage by Medicare) from California, Florida, New York, Ohio, and Pennsylvania. We obtained and compiled 1999-2011 data from these state Medicaid programs (constituting about 38% of nationwide Medicaid enrollment), together with corresponding national Medicare data for dually-enrolled beneficiaries. This descriptive study examined longitudinal patterns in: dispensed prescriptions by state, by quarter; and inpatient hospitalizations by federal benefit, state, and age group. We further examined discrepancies between demographic characteristics and disease states, in particular frequencies of pregnancy complications among men and women beyond childbearing age, and prostate cancers among women. Results: Dispensed prescriptions generally increased steadily and consistently over time, suggesting that these claims may be complete. A commercially-available National Drug Code lookup database was able to identify the dispensed drug for 95.2-99.4% of these claims. Because of co-coverage by Medicare, Medicaid data appeared to miss a substantial number of hospitalizations among beneficiaries ≥ 45 years of age. Pregnancy complication diagnoses were rare in males and in females ≥ 60 years of age, and prostate cancer diagnoses were rare in females. Conclusions: CMS claims from five large states obtained directly from CMS and its contractors appeared to be of high quality. Researchers using Medicaid data to study hospital outcomes should obtain supplemental Medicare data on dual enrollees, even for non-elders. Trial Registration: Not applicable.
Cognitive dysfunction in schizophrenia is well established with neuropsychological batteries, whi... more Cognitive dysfunction in schizophrenia is well established with neuropsychological batteries, which have assessed multiple domains indicating diffuse deficits especially in processing related to frontotemporal systems. Two studies are reported examining the feasibility of the computerized neurocognitive scan to assess differential deficits in schizophrenia. In Study 1, we tested 53 patients and 71 controls with the traditional and computerized assessments counterbalanced in order. Both showed comparable generalized impairment in schizophrenia with differential deficits in executive functions and memory. The profile was replicated in Study 2 in a new sample of 68 patients and 37 controls, receiving only the computerized scan. The combined sample showed robust correlations between performance on both speed and accuracy measures of the neurocognitive scan and clinical variables, including premorbid adjustment, onset age, illness duration, quality of life, and severity of negative symptoms. These correlations were higher and more prevalent in women than men, who showed correlations predominantly for speed rather than accuracy. Neuroleptic exposure was associated with poorer performance only for speed of memory processing, and in men, this association was seen only for typical neuroleptics. We conclude that the computerized neurocognitive scan can be applied reliably in people with schizophrenia, yielding data that support its construct and criterion validity.
Journal of the American Academy of Child and Adolescent Psychiatry, 2017
Increasing evidence implicates advanced paternal age at offspring birth in neuropsychiatric disor... more Increasing evidence implicates advanced paternal age at offspring birth in neuropsychiatric disorders. Advanced maternal age has also been associated with schizophrenia and other neurodevelopmental disorders, whereas younger maternal age has been linked with behavioral disorders. Few studies have considered the specificity of the associations with respect to comorbidity. In addition, most prior studies have been conducted in clinical samples or registries that may reflect more severe forms of psychopathology. The aim of this research is to examine the independent and joint associations of maternal and paternal age with specific subtypes of psychopathology in offspring in a pediatric sample of adolescents with emergent psychiatric syndromes. A total of 8,725 youths (aged 8-21 years) from the Philadelphia Neurodevelopmental Cohort were included in the analyses. Logistic regression models with parental age predicting offspring psychopathology were adjusted for sociodemographic factors ...
There is a strong need to better understand the neurobiology of juvenile sociability (tendency to... more There is a strong need to better understand the neurobiology of juvenile sociability (tendency to seek social interaction), a phenotype of central relevance to autism spectrum disorders (ASD). Although numerous genetic mouse models of ASD showing reduced sociability have been reported, and certain brain regions, such as the amygdala, have been implicated in sociability, there has been little emphasis on delineating brain structures and circuits activated during social interactions in the critical juvenile period of the mouse strain that serves as the most common genetic background for these models-the highly sociable C57BL/6J (B6) strain. We measured expression of the immediate early genes Fos and Egr-1 to map activation of brain regions following the Social Approach Test (SAT) in juvenile male B6 mice. We hypothesized that juvenile B6 mice would show activation of the amygdala during social interactions. The basoloateral amygdala (BLA) was activated by social exposure in highly sociable, 4-week-old B6 mice. In light of these data, and the many lines of evidence indicating alteration of amygdala circuits in human ASD, future studies are warranted to assess structural and functional alterations in the BLA, particularly at BLA synapses, in various mouse models of ASD.
We conducted high-dimensional propensity score-adjusted cohort studies to examine whether thiazol... more We conducted high-dimensional propensity score-adjusted cohort studies to examine whether thiazolidinedione use with a statin or fibrate was associated with an increased risk of severe hypoglycemia. We found that concomitant therapy with a thiazolidinedione+fibrate was associated with a generally delayed increased risk of severe hypoglycemia.
Traditional "paper-and-pencil" testing is imprecise in measuring speed and hence limite... more Traditional "paper-and-pencil" testing is imprecise in measuring speed and hence limited in assessing performance efficiency, but computerized testing permits precision in measuring itemwise response time. We present a method of scoring performance efficiency (combining information from accuracy and speed) at the item level. Using a community sample of 9,498 youths age 8-21, we calculated item-level efficiency scores on 4 neurocognitive tests, and compared the concurrent, convergent, discriminant, and predictive validity of these scores with simple averaging of standardized speed and accuracy-summed scores. Concurrent validity was measured by the scores' abilities to distinguish men from women and their correlations with age; convergent and discriminant validity were measured by correlations with other scores inside and outside of their neurocognitive domains; predictive validity was measured by correlations with brain volume in regions associated with the specific neu...
Reports on the association between statins and memory impairment are inconsistent. To assess whet... more Reports on the association between statins and memory impairment are inconsistent. To assess whether statin users show acute decline in memory compared with nonusers and with users of nonstatin lipid-lowering drugs (LLDs). Using The Health Improvement Network database during January 13, 1987, through December 16, 2013, a retrospective cohort study compared 482 543 statin users with 2 control groups: 482 543 matched nonusers of any LLDs and all 26 484 users of nonstatin LLDs. A case-crossover study of 68 028 patients with incident acute memory loss evaluated exposure to statins during the period immediately before the outcome vs 3 earlier periods. Analysis was conducted from July 7, 2013, through January 15, 2015. When compared with matched nonusers of any LLDs (using odds ratio [95% CI]), a strong association was present between first exposure to statins and incident acute memory loss diagnosed within 30 days immediately following exposure (fully adjusted, 4.40; 3.01-6.41). This ass...
The aim of this study was to determine whether a potential pharmacokinetic interaction between wa... more The aim of this study was to determine whether a potential pharmacokinetic interaction between warfarin and orally administered anti-infectives increases the risk of hospitalization for gastrointestinal (GI) bleeding in warfarin users. We conducted a nested case-control and case-crossover study using US Medicaid data. Logistic regression was used to determine the association between GI bleeding and prior use of ciprofloxacin, levofloxacin, gatifloxacin, co-trimoxazole, or fluconazole vs. no exposure and also vs. use of cephalexin, which would not be expected to interact with warfarin. All of the anti-infectives examined were associated with elevated odds ratios (ORs) when compared to no exposure to these drugs. With cephalexin data as the reference, the ORs for co-trimoxazole (OR: 1.68 (95% confidence interval (CI): 1.21-2.33) in the prior 6-10 days) and fluconazole (OR: 2.09 (95% CI: 1.34-3.26) in the prior 11-15 days) were significantly elevated. Warfarin users who had received an...
There is controversy and little information about whether individual proton pump inhibitors (PPIs... more There is controversy and little information about whether individual proton pump inhibitors (PPIs) differentially alter the effectiveness of clopidogrel in reducing ischemic stroke risk. We, therefore, aimed to elucidate the risk of ischemic stroke among concomitant users of clopidogrel and individual PPIs. We conducted a propensity score-adjusted cohort study of adult new users of clopidogrel, using 1999 to 2009 Medicaid claims from 5 large states. Exposures were defined by prescriptions for esomeprazole, lansoprazole, omeprazole, rabeprazole, and pantoprazole-with pantoprazole serving as the referent. The end point was hospitalization for acute ischemic stroke, defined by International Classification of Diseases Ninth Revision Clinical Modification codes in the principal position on inpatient claims, within 180 days of concomitant therapy initiation. Among 325 559 concomitant users of clopidogrel and a PPI, we identified 1667 ischemic strokes for an annual incidence of 2.4% (95% c...
Journal of clinical & experimental cardiology, 2013
Antipsychotic drugs have been linked to QT-interval prolongation, a presumed marker of cardiac ri... more Antipsychotic drugs have been linked to QT-interval prolongation, a presumed marker of cardiac risk, and torsade de pointes. To examine the associations between antipsychotics and 1) outpatient-originated sudden cardiac death and ventricular arrhythmia (SD/VA) and 2) all-cause death. Two retrospective cohort studies. Medicaid programs of California, Florida, New York, Ohio and Pennsylvania. Incident antipsychotic users aged 30-75 years. 1) Incident, first-listed emergency department or principal inpatient SD/VA diagnoses; and 2) death reported in the Social Security Administration Death Master File. Among 459,614 incident antipsychotic users, the incidences of SD/VA and death were 3.4 and 35.1 per 1,000 person-years, respectively. Compared to olanzapine as the referent, adjusted hazard ratios (HRs) for SD/VA were 2.06 (95% CI, 1.20-3.53) for chlorpromazine, 1.72 (1.28-2.31) for haloperidol, and 0.73 (0.57-0.93) for quetiapine. Adjusted HRs for perphenazine and risperidone were consi...
To examine the association between exposure to antidepressants and emergency department or inpati... more To examine the association between exposure to antidepressants and emergency department or inpatient admission for sudden cardiac death and ventricular arrhythmia (SD/VA), and to examine the impact of dose and cytochrome P-450 inhibition. A cohort study was conducted using 1999-2003 Medicaid claims data from beneficiaries of five large states, supplemented with Medicare claims for dually eligible individuals. Exposures were prescription claims for antidepressants of interest or a reference antidepressant. Outcomes were incident first-listed emergency department or principal inpatient diagnoses indicative of SD/VA originating in the outpatient setting, an outcome previously found to have a positive predictive value of 85%. In 1.3 million person-years of antidepressant exposure, we identified 4222 SD/VA outcomes for a rate of 3.3/1000 person-years (95%CI, 3.2-3.4). Compared with paroxetine (a referent with a putatively favorable cardiovascular risk profile), adjusted hazard ratios (HR...
The objective of this study was to evaluate whether orally administered anti-infectives increase ... more The objective of this study was to evaluate whether orally administered anti-infectives increase the risk of severe hypoglycemia in users of glipizide or glyburide. We performed two case-control studies and two case-crossover studies using US Medicaid data. All the anti-infectives examined were associated with an elevated risk of severe hypoglycemia. Using cephalexin as the reference category, in glipizide users, statistically significant associations were found with co-trimoxazole (odds ratio (OR) = 3.14; 95% confidence interval (CI): 1.83-5.37); clarithromycin (OR = 2.90; 95% CI: 1.69-4.98); fluconazole (OR = 2.53; 95% CI: 1.23-5.23); and levofloxacin (OR = 2.09; 95% CI: 1.35-3.25). In glyburide users, with cephalexin as the reference, statistically significant associations were found with clarithromycin (OR = 5.02; 95% CI: 3.35-7.54); levofloxacin (OR = 2.83; 95% CI: 1.73-4.62); co-trimoxazole (OR = 2.68; 95% CI: 1.59-4.52); fluconazole (OR = 2.20; 95% CI: 1.04-4.68); and ciprofl...
The ability to reason with language is a highly valued cognitive capacity that correlates with IQ... more The ability to reason with language is a highly valued cognitive capacity that correlates with IQ measures and is sensitive to damage in language areas. The Penn Verbal Reasoning Test (PVRT) is a 29-item computerized test for measuring abstract analogical reasoning abilities using language. The full test can take over half an hour to administer, which limits its applicability in large-scale studies. We previously described a procedure for abbreviating a clinical rating scale and a modified procedure for reducing tests with a large number of items. Here we describe the application of the modified method to reducing the number of items in the PVRT to a parsimonious subset of items that accurately predicts the total score. As in our previous reduction studies, a split sample is used for model fitting and validation, with cross-validation to verify results. We find that an 8-item scale predicts the total 29-item score well, achieving a correlation of .9145 for the reduced form for the m...
II al Objective: This study examined whether subcortical volumes of the basal ganglia and thalamu... more II al Objective: This study examined whether subcortical volumes of the basal ganglia and thalamus in schizophrenic patients are related to neuroleptic exposure and symptom severity. Method: Basal ganglia substructures and thalamic volumes were measured with magnetic resonance imaging in 96 patients with schizophrenia (50 men and 46 women) and 128 healthy comparison subjects (60 men and 68 women). Twenty-one of the patients were neuroleptic-naive; of the 75 previously treated patients, 48 had received typical neuroleptics only, and 27 had received typical and atypical neuroleptics. The relation of volume measures to treatment status, exposure to neuroleptics, and symptoms was examined. Results: The neuroleptic-naive patients did not differ from the healthy comparison subjects in subcortical volumes except for lower thalamic volume. In the neuroleptic-naive group, volumes did not correlate with severity of negative symptoms, but higher volumes in both the thalamus and the putamen were associated with more severe positive symptoms.. The previously treated group showed higher volumes in the putamen and globus pallidus than the healthy comparison subjects and the neuroleptic-naive patients. In the treated group, a higher dose of a typical neuroleptic was associated with higher caudate, putamen, and thalamus volumes, whereas a higher dose of an atypical neuroleptic was associated only with higher thalamic volume. Higher subcortical volumes were mildly associated with g.r.eater severity of both negative and positive sympto!Jls. ConciUsiC;;;s: Increased subcortical volumes in treated schizophrenic patients seem to be medication-induced hypertrophy. This hypertrophy could reflect structural adaptation to receptor blockade and may moderate the effects of neuroleptic treatment.
The continuum view of the psychosis spectrum (PS) implies that, in population-based samples, PS s... more The continuum view of the psychosis spectrum (PS) implies that, in population-based samples, PS symptoms should be associated with neural abnormalities similar to those found in help-seeking clinical risk individuals and in schizophrenia. To our knowledge, functional neuroimaging has not previously been applied in large population-based PS samples and can help us understand the neural architecture of psychosis more broadly and identify brain phenotypes beyond symptoms that are associated with the extended psychosis phenotype. To examine the categorical and dimensional relationships of PS symptoms to prefrontal hypoactivation during working memory and to amygdala hyperactivation during threat emotion processing. The Philadelphia Neurodevelopmental Cohort is a genotyped, prospectively accrued, population-based sample of almost 10 000 youths who received a structured psychiatric evaluation and a computerized neurocognitive battery. The study was conducted at an academic and children...
To measure the incidence of cancer in patients with psoriasis, stratified by the severity of thei... more To measure the incidence of cancer in patients with psoriasis, stratified by the severity of their disease. A cohort study. Administrative claims records obtained from Medicaid programs in 3 US states. All individuals in the claims database who qualified for 1 of the 5 following groups: severe psoriasis as defined by treatment with systemic medication, less severe psoriasis, severe eczema, history of organ transplantation, and hypertension. A diagnosis of cancer. Individuals with severe psoriasis were more likely to develop a malignancy than those with hypertension (risk ratio, 1.78; 95% confidence interval [CI], 1.32-2.40). The risk of malignancy in the severe psoriasis group approaches that in patients with organ transplants (risk ratio, 2.12; 95% CI, 1.80-2.50). Most of these cancers were nonmelanoma skin cancers and lymphoproliferative malignancies. Those with less severe psoriasis were only slightly more likely to develop a new malignancy than those with hypertension (risk rati...
Multiple lines of evidence point to glutamatergic signaling in the postsynaptic density (PSD) as ... more Multiple lines of evidence point to glutamatergic signaling in the postsynaptic density (PSD) as a pathophysiologic mechanism in schizophrenia. Integral to PSD glutamatergic signaling is reciprocal interplay between GluN and mGluR5 signaling. We examined agonist-induced mGluR5 signaling in the postmortem dorsolateral prefrontal cortex (DLPFC) derived from 17 patients and age-matched and sex-matched controls. The patient group showed a striking reduction in mGluR5 signaling, manifested by decreases in Gq/11 coupling and association with PI3K and Homer compared to controls (p < 0.01 for all). This was accompanied by increases in serine and tyrosine phosphorylation of mGluR5, which can decrease mGluR5 activity via desensitization (p < 0.01). In addition, we find altered protein-protein interaction (PPI) of mGluR5 with RGS4, norbin, Preso 1 and tamalin, which can also attenuate mGluR5 activity. We previously reported molecular underpinnings of GluN hypofunction (decreased GluN2 ph...
Warfarin and antihyperlipidemics are commonly co-prescribed. Some antihyperlipidemics may inhibit... more Warfarin and antihyperlipidemics are commonly co-prescribed. Some antihyperlipidemics may inhibit warfarin deactivation via the hepatic cytochrome P450 system. Therefore, antihyperlipidemic discontinuation has been hypothesized to result in underanticoagulation, as warfarin metabolism is no longer inhibited. We quantified the risk of venous thromboembolism (VTE) and ischemic stroke (IS) due to statin and fibrate discontinuation in warfarin users, in which warfarin was initially dose-titrated during ongoing antihyperlipidemic therapy. Using 1999-2011 United States Medicaid claims among 69 million beneficiaries, we conducted a set of bidirectional self-controlled case series studies-one for each antihyperlipidemic. Outcomes were hospital admissions for VTE/IS. The risk segment was a maximum of 90 days immediately following antihyperlipidemic discontinuation, the exposure of interest. Time-varying confounders were included in conditional Poisson models. We identified 629 study eligible...
To examine the association between individual antidiabetic sulfonylureas and outpatient-originati... more To examine the association between individual antidiabetic sulfonylureas and outpatient-originating sudden cardiac arrest and ventricular arrhythmia (SCA/VA). We conducted a retrospective cohort study using 1999-2010 U.S. Medicaid claims from five large states. Exposures were determined by incident use of glyburide, glimepiride, or glipizide. Glipizide served as the reference exposure, as its effects are believed to be highly pancreas specific. Outcomes were ascertained by a validated ICD-9-based algorithm indicative of SCA/VA (positive predictive value ∼85%). Potential confounding was addressed by adjustment for multinomial high-dimensional propensity scores included as continuous variables in a Cox proportional hazards model. Of sulfonylurea users under study ( = 519,272), 60.3% were female and 34.9% non-Hispanic Caucasian, and the median age was 58.0 years. In 176,889 person-years of sulfonylurea exposure, we identified 632 SCA/VA events (50.5% were immediately fatal) for a crude...
To examine the comparative safety of individual NSAIDs when given concomitantly with clopidogrel.... more To examine the comparative safety of individual NSAIDs when given concomitantly with clopidogrel. We conducted a retrospective cohort study using Medicaid claims from five US states during 1999-2010, supplemented with Medicare claims for dual-enrollees. The exposure of interest was the first concomitant use of clopidogrel and one of the 10 selected NSAIDs after a 1-year baseline period. The outcomes were: all-cause mortality; acute myocardial infarction (AMI)/ischemic stroke; and gastrointestinal bleeding (GIB)/intracranial hemorrhage (ICH). We calculated the hazard ratio of each NSAID for each outcome, with ibuprofen as the reference drug, using high-dimensional propensity score-adjusted proportional-hazards regression models. Of 1,060,412 clopidogrel users, 268,114 concomitant NSAID users met inclusion/exclusion criteria, contributing 48,483 person-years. We observed 2,463 deaths, 2,822 AMI/ischemic stroke outcomes, and 2,620 GIB/ICH outcomes, for unadjusted incidence rates of 50....
Background: Administrative claims of United States Centers for Medicare and Medicaid Services (CM... more Background: Administrative claims of United States Centers for Medicare and Medicaid Services (CMS) beneficiaries have long been used in non-experimental research. While CMS performs in-house checks of these claims, little is known of their quality for conducting pharmacoepidemiologic research. We performed exploratory analyses of the quality of Medicaid and Medicare data obtained from CMS and its contractors. Methods: Our study population consisted of Medicaid beneficiaries (with and without dual coverage by Medicare) from California, Florida, New York, Ohio, and Pennsylvania. We obtained and compiled 1999-2011 data from these state Medicaid programs (constituting about 38% of nationwide Medicaid enrollment), together with corresponding national Medicare data for dually-enrolled beneficiaries. This descriptive study examined longitudinal patterns in: dispensed prescriptions by state, by quarter; and inpatient hospitalizations by federal benefit, state, and age group. We further examined discrepancies between demographic characteristics and disease states, in particular frequencies of pregnancy complications among men and women beyond childbearing age, and prostate cancers among women. Results: Dispensed prescriptions generally increased steadily and consistently over time, suggesting that these claims may be complete. A commercially-available National Drug Code lookup database was able to identify the dispensed drug for 95.2-99.4% of these claims. Because of co-coverage by Medicare, Medicaid data appeared to miss a substantial number of hospitalizations among beneficiaries ≥ 45 years of age. Pregnancy complication diagnoses were rare in males and in females ≥ 60 years of age, and prostate cancer diagnoses were rare in females. Conclusions: CMS claims from five large states obtained directly from CMS and its contractors appeared to be of high quality. Researchers using Medicaid data to study hospital outcomes should obtain supplemental Medicare data on dual enrollees, even for non-elders. Trial Registration: Not applicable.
Cognitive dysfunction in schizophrenia is well established with neuropsychological batteries, whi... more Cognitive dysfunction in schizophrenia is well established with neuropsychological batteries, which have assessed multiple domains indicating diffuse deficits especially in processing related to frontotemporal systems. Two studies are reported examining the feasibility of the computerized neurocognitive scan to assess differential deficits in schizophrenia. In Study 1, we tested 53 patients and 71 controls with the traditional and computerized assessments counterbalanced in order. Both showed comparable generalized impairment in schizophrenia with differential deficits in executive functions and memory. The profile was replicated in Study 2 in a new sample of 68 patients and 37 controls, receiving only the computerized scan. The combined sample showed robust correlations between performance on both speed and accuracy measures of the neurocognitive scan and clinical variables, including premorbid adjustment, onset age, illness duration, quality of life, and severity of negative symptoms. These correlations were higher and more prevalent in women than men, who showed correlations predominantly for speed rather than accuracy. Neuroleptic exposure was associated with poorer performance only for speed of memory processing, and in men, this association was seen only for typical neuroleptics. We conclude that the computerized neurocognitive scan can be applied reliably in people with schizophrenia, yielding data that support its construct and criterion validity.
Journal of the American Academy of Child and Adolescent Psychiatry, 2017
Increasing evidence implicates advanced paternal age at offspring birth in neuropsychiatric disor... more Increasing evidence implicates advanced paternal age at offspring birth in neuropsychiatric disorders. Advanced maternal age has also been associated with schizophrenia and other neurodevelopmental disorders, whereas younger maternal age has been linked with behavioral disorders. Few studies have considered the specificity of the associations with respect to comorbidity. In addition, most prior studies have been conducted in clinical samples or registries that may reflect more severe forms of psychopathology. The aim of this research is to examine the independent and joint associations of maternal and paternal age with specific subtypes of psychopathology in offspring in a pediatric sample of adolescents with emergent psychiatric syndromes. A total of 8,725 youths (aged 8-21 years) from the Philadelphia Neurodevelopmental Cohort were included in the analyses. Logistic regression models with parental age predicting offspring psychopathology were adjusted for sociodemographic factors ...
There is a strong need to better understand the neurobiology of juvenile sociability (tendency to... more There is a strong need to better understand the neurobiology of juvenile sociability (tendency to seek social interaction), a phenotype of central relevance to autism spectrum disorders (ASD). Although numerous genetic mouse models of ASD showing reduced sociability have been reported, and certain brain regions, such as the amygdala, have been implicated in sociability, there has been little emphasis on delineating brain structures and circuits activated during social interactions in the critical juvenile period of the mouse strain that serves as the most common genetic background for these models-the highly sociable C57BL/6J (B6) strain. We measured expression of the immediate early genes Fos and Egr-1 to map activation of brain regions following the Social Approach Test (SAT) in juvenile male B6 mice. We hypothesized that juvenile B6 mice would show activation of the amygdala during social interactions. The basoloateral amygdala (BLA) was activated by social exposure in highly sociable, 4-week-old B6 mice. In light of these data, and the many lines of evidence indicating alteration of amygdala circuits in human ASD, future studies are warranted to assess structural and functional alterations in the BLA, particularly at BLA synapses, in various mouse models of ASD.
We conducted high-dimensional propensity score-adjusted cohort studies to examine whether thiazol... more We conducted high-dimensional propensity score-adjusted cohort studies to examine whether thiazolidinedione use with a statin or fibrate was associated with an increased risk of severe hypoglycemia. We found that concomitant therapy with a thiazolidinedione+fibrate was associated with a generally delayed increased risk of severe hypoglycemia.
Traditional "paper-and-pencil" testing is imprecise in measuring speed and hence limite... more Traditional "paper-and-pencil" testing is imprecise in measuring speed and hence limited in assessing performance efficiency, but computerized testing permits precision in measuring itemwise response time. We present a method of scoring performance efficiency (combining information from accuracy and speed) at the item level. Using a community sample of 9,498 youths age 8-21, we calculated item-level efficiency scores on 4 neurocognitive tests, and compared the concurrent, convergent, discriminant, and predictive validity of these scores with simple averaging of standardized speed and accuracy-summed scores. Concurrent validity was measured by the scores' abilities to distinguish men from women and their correlations with age; convergent and discriminant validity were measured by correlations with other scores inside and outside of their neurocognitive domains; predictive validity was measured by correlations with brain volume in regions associated with the specific neu...
Reports on the association between statins and memory impairment are inconsistent. To assess whet... more Reports on the association between statins and memory impairment are inconsistent. To assess whether statin users show acute decline in memory compared with nonusers and with users of nonstatin lipid-lowering drugs (LLDs). Using The Health Improvement Network database during January 13, 1987, through December 16, 2013, a retrospective cohort study compared 482 543 statin users with 2 control groups: 482 543 matched nonusers of any LLDs and all 26 484 users of nonstatin LLDs. A case-crossover study of 68 028 patients with incident acute memory loss evaluated exposure to statins during the period immediately before the outcome vs 3 earlier periods. Analysis was conducted from July 7, 2013, through January 15, 2015. When compared with matched nonusers of any LLDs (using odds ratio [95% CI]), a strong association was present between first exposure to statins and incident acute memory loss diagnosed within 30 days immediately following exposure (fully adjusted, 4.40; 3.01-6.41). This ass...
The aim of this study was to determine whether a potential pharmacokinetic interaction between wa... more The aim of this study was to determine whether a potential pharmacokinetic interaction between warfarin and orally administered anti-infectives increases the risk of hospitalization for gastrointestinal (GI) bleeding in warfarin users. We conducted a nested case-control and case-crossover study using US Medicaid data. Logistic regression was used to determine the association between GI bleeding and prior use of ciprofloxacin, levofloxacin, gatifloxacin, co-trimoxazole, or fluconazole vs. no exposure and also vs. use of cephalexin, which would not be expected to interact with warfarin. All of the anti-infectives examined were associated with elevated odds ratios (ORs) when compared to no exposure to these drugs. With cephalexin data as the reference, the ORs for co-trimoxazole (OR: 1.68 (95% confidence interval (CI): 1.21-2.33) in the prior 6-10 days) and fluconazole (OR: 2.09 (95% CI: 1.34-3.26) in the prior 11-15 days) were significantly elevated. Warfarin users who had received an...
There is controversy and little information about whether individual proton pump inhibitors (PPIs... more There is controversy and little information about whether individual proton pump inhibitors (PPIs) differentially alter the effectiveness of clopidogrel in reducing ischemic stroke risk. We, therefore, aimed to elucidate the risk of ischemic stroke among concomitant users of clopidogrel and individual PPIs. We conducted a propensity score-adjusted cohort study of adult new users of clopidogrel, using 1999 to 2009 Medicaid claims from 5 large states. Exposures were defined by prescriptions for esomeprazole, lansoprazole, omeprazole, rabeprazole, and pantoprazole-with pantoprazole serving as the referent. The end point was hospitalization for acute ischemic stroke, defined by International Classification of Diseases Ninth Revision Clinical Modification codes in the principal position on inpatient claims, within 180 days of concomitant therapy initiation. Among 325 559 concomitant users of clopidogrel and a PPI, we identified 1667 ischemic strokes for an annual incidence of 2.4% (95% c...
Journal of clinical & experimental cardiology, 2013
Antipsychotic drugs have been linked to QT-interval prolongation, a presumed marker of cardiac ri... more Antipsychotic drugs have been linked to QT-interval prolongation, a presumed marker of cardiac risk, and torsade de pointes. To examine the associations between antipsychotics and 1) outpatient-originated sudden cardiac death and ventricular arrhythmia (SD/VA) and 2) all-cause death. Two retrospective cohort studies. Medicaid programs of California, Florida, New York, Ohio and Pennsylvania. Incident antipsychotic users aged 30-75 years. 1) Incident, first-listed emergency department or principal inpatient SD/VA diagnoses; and 2) death reported in the Social Security Administration Death Master File. Among 459,614 incident antipsychotic users, the incidences of SD/VA and death were 3.4 and 35.1 per 1,000 person-years, respectively. Compared to olanzapine as the referent, adjusted hazard ratios (HRs) for SD/VA were 2.06 (95% CI, 1.20-3.53) for chlorpromazine, 1.72 (1.28-2.31) for haloperidol, and 0.73 (0.57-0.93) for quetiapine. Adjusted HRs for perphenazine and risperidone were consi...
To examine the association between exposure to antidepressants and emergency department or inpati... more To examine the association between exposure to antidepressants and emergency department or inpatient admission for sudden cardiac death and ventricular arrhythmia (SD/VA), and to examine the impact of dose and cytochrome P-450 inhibition. A cohort study was conducted using 1999-2003 Medicaid claims data from beneficiaries of five large states, supplemented with Medicare claims for dually eligible individuals. Exposures were prescription claims for antidepressants of interest or a reference antidepressant. Outcomes were incident first-listed emergency department or principal inpatient diagnoses indicative of SD/VA originating in the outpatient setting, an outcome previously found to have a positive predictive value of 85%. In 1.3 million person-years of antidepressant exposure, we identified 4222 SD/VA outcomes for a rate of 3.3/1000 person-years (95%CI, 3.2-3.4). Compared with paroxetine (a referent with a putatively favorable cardiovascular risk profile), adjusted hazard ratios (HR...
The objective of this study was to evaluate whether orally administered anti-infectives increase ... more The objective of this study was to evaluate whether orally administered anti-infectives increase the risk of severe hypoglycemia in users of glipizide or glyburide. We performed two case-control studies and two case-crossover studies using US Medicaid data. All the anti-infectives examined were associated with an elevated risk of severe hypoglycemia. Using cephalexin as the reference category, in glipizide users, statistically significant associations were found with co-trimoxazole (odds ratio (OR) = 3.14; 95% confidence interval (CI): 1.83-5.37); clarithromycin (OR = 2.90; 95% CI: 1.69-4.98); fluconazole (OR = 2.53; 95% CI: 1.23-5.23); and levofloxacin (OR = 2.09; 95% CI: 1.35-3.25). In glyburide users, with cephalexin as the reference, statistically significant associations were found with clarithromycin (OR = 5.02; 95% CI: 3.35-7.54); levofloxacin (OR = 2.83; 95% CI: 1.73-4.62); co-trimoxazole (OR = 2.68; 95% CI: 1.59-4.52); fluconazole (OR = 2.20; 95% CI: 1.04-4.68); and ciprofl...
The ability to reason with language is a highly valued cognitive capacity that correlates with IQ... more The ability to reason with language is a highly valued cognitive capacity that correlates with IQ measures and is sensitive to damage in language areas. The Penn Verbal Reasoning Test (PVRT) is a 29-item computerized test for measuring abstract analogical reasoning abilities using language. The full test can take over half an hour to administer, which limits its applicability in large-scale studies. We previously described a procedure for abbreviating a clinical rating scale and a modified procedure for reducing tests with a large number of items. Here we describe the application of the modified method to reducing the number of items in the PVRT to a parsimonious subset of items that accurately predicts the total score. As in our previous reduction studies, a split sample is used for model fitting and validation, with cross-validation to verify results. We find that an 8-item scale predicts the total 29-item score well, achieving a correlation of .9145 for the reduced form for the m...
II al Objective: This study examined whether subcortical volumes of the basal ganglia and thalamu... more II al Objective: This study examined whether subcortical volumes of the basal ganglia and thalamus in schizophrenic patients are related to neuroleptic exposure and symptom severity. Method: Basal ganglia substructures and thalamic volumes were measured with magnetic resonance imaging in 96 patients with schizophrenia (50 men and 46 women) and 128 healthy comparison subjects (60 men and 68 women). Twenty-one of the patients were neuroleptic-naive; of the 75 previously treated patients, 48 had received typical neuroleptics only, and 27 had received typical and atypical neuroleptics. The relation of volume measures to treatment status, exposure to neuroleptics, and symptoms was examined. Results: The neuroleptic-naive patients did not differ from the healthy comparison subjects in subcortical volumes except for lower thalamic volume. In the neuroleptic-naive group, volumes did not correlate with severity of negative symptoms, but higher volumes in both the thalamus and the putamen were associated with more severe positive symptoms.. The previously treated group showed higher volumes in the putamen and globus pallidus than the healthy comparison subjects and the neuroleptic-naive patients. In the treated group, a higher dose of a typical neuroleptic was associated with higher caudate, putamen, and thalamus volumes, whereas a higher dose of an atypical neuroleptic was associated only with higher thalamic volume. Higher subcortical volumes were mildly associated with g.r.eater severity of both negative and positive sympto!Jls. ConciUsiC;;;s: Increased subcortical volumes in treated schizophrenic patients seem to be medication-induced hypertrophy. This hypertrophy could reflect structural adaptation to receptor blockade and may moderate the effects of neuroleptic treatment.
The continuum view of the psychosis spectrum (PS) implies that, in population-based samples, PS s... more The continuum view of the psychosis spectrum (PS) implies that, in population-based samples, PS symptoms should be associated with neural abnormalities similar to those found in help-seeking clinical risk individuals and in schizophrenia. To our knowledge, functional neuroimaging has not previously been applied in large population-based PS samples and can help us understand the neural architecture of psychosis more broadly and identify brain phenotypes beyond symptoms that are associated with the extended psychosis phenotype. To examine the categorical and dimensional relationships of PS symptoms to prefrontal hypoactivation during working memory and to amygdala hyperactivation during threat emotion processing. The Philadelphia Neurodevelopmental Cohort is a genotyped, prospectively accrued, population-based sample of almost 10 000 youths who received a structured psychiatric evaluation and a computerized neurocognitive battery. The study was conducted at an academic and children...
To measure the incidence of cancer in patients with psoriasis, stratified by the severity of thei... more To measure the incidence of cancer in patients with psoriasis, stratified by the severity of their disease. A cohort study. Administrative claims records obtained from Medicaid programs in 3 US states. All individuals in the claims database who qualified for 1 of the 5 following groups: severe psoriasis as defined by treatment with systemic medication, less severe psoriasis, severe eczema, history of organ transplantation, and hypertension. A diagnosis of cancer. Individuals with severe psoriasis were more likely to develop a malignancy than those with hypertension (risk ratio, 1.78; 95% confidence interval [CI], 1.32-2.40). The risk of malignancy in the severe psoriasis group approaches that in patients with organ transplants (risk ratio, 2.12; 95% CI, 1.80-2.50). Most of these cancers were nonmelanoma skin cancers and lymphoproliferative malignancies. Those with less severe psoriasis were only slightly more likely to develop a new malignancy than those with hypertension (risk rati...
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Papers by Warren Bilker