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Publications (11)43.2 Total impact

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    ABSTRACT: A study was undertaken to determine whether psychiatric disorders associated with suicide are more common in incident epilepsy than in matched controls without epilepsy, before and after epilepsy diagnosis. A matched, longitudinal cohort study was conducted in the UK General Practice Research Database. A total of 3,773 cases diagnosed with epilepsy between the ages of 10 and 60 years were compared to 14,025 controls matched by year of birth, sex, general practice, and years of medical records before the index date. We examined first diagnosis of psychosis, depression, anxiety, and suicidality in each of the 3 years before and after the index date and annual prevalence of suicide. Referent diagnoses were eczema and acute surgery. The incidence rate ratio (IRR) was calculated for each year in the study period; the prevalence ratio (PR) was calculated for suicidality. The IRR of psychosis, depression, and anxiety was significantly increased for all years before epilepsy diagnosis (IRR, 1.5-15.7) and after diagnosis (IRR, 2.2-10.9) and for suicidality before epilepsy diagnosis (IRR, 3.1-4.5) and 1 year after diagnosis (IRR, 5.3). The PR was increased for suicide attempt before epilepsy onset (PR, 2.6-5.2) and after onset (PR, 2.4-5.6). Eczema and acute surgery were both associated with epilepsy in the first and third year after diagnosis. Epilepsy is associated with an increased onset of psychiatric disorders and suicide before and after epilepsy diagnosis. These relations suggest common underlying pathophysiological mechanisms that both lower seizure threshold and increase risk for psychiatric disorders and suicide.
    Annals of Neurology 03/2012; 72(2):184-91. · 11.19 Impact Factor
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    ABSTRACT: High doses of gabapentin were associated with pancreatic acinar cell tumors in male Wistar rats, but there is little published epidemiological data regarding gabapentin and carcinogenicity. We explored the association between gabapentin and cancer in a US medical care program and followed up nominally significant associations in a UK primary care database. In the US Kaiser Permanente Northern California (KPNC) health system, we performed nested case-control analyses of gabapentin and 55 cancer sites and all cancers combined using conditional logistic regression. Up to 10 controls were matched to each case on year of birth, sex, and year of cohort entry. No other covariates were included in models. Only dispensings for gabapentin 2 years or more before index date were considered. Nominally significant associations with an OR > 1.00 and p < 0.05 for three or more dispensings versus no dispensings were followed up by similar nested case-control analyses in the UK General Practice Research Database (GPRD), adjusting for potential indications for gabapentin and risk factors for the specific cancers. The following analyses had OR > 1.00 and p < 0.05 for three or more dispensings of gabapentin versus no dispensing (2-year lag) in KPNC and were also examined in the GPRD: all cancers, breast, lung and bronchus, urinary bladder, kidney/renal pelvis, stomach, anus/anal canal/anorectum, penis, and other nervous system. These cancers were not statistically significantly associated with gabapentin in the GPRD case-control studies (2-year lag). The GPRD and KPNC studies did not identify a statistically significant increased risk of pancreatic cancer with more than two prescriptions of gabapentin in the 2-year lagged analyses. The epidemiological data in a US cohort with up to 12 years of follow-up and a UK cohort with up to 15 years of follow-up do not support a carcinogenic effect of gabapentin use. However, the confidence intervals for some analyses were wide, and an important effect cannot be confidently excluded.
    Pharmacoepidemiology and Drug Safety 12/2011; 21(2):214-25. · 2.90 Impact Factor
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    ABSTRACT: The FDA provides guidance regarding pre-marketing liver chemistry subject stopping criteria. This study was undertaken to determine the background rates of liver chemistry abnormalities in pediatric clinical trials for conditions with and without underlying liver disease (LD). The study included 5410 subjects aged 0-18years in 24 trials for conditions without LD. 3756 pediatric subjects in 14 trials for conditions with LD (malaria, HIV, HBV) were also analyzed. Prevalence and incidence of abnormal liver chemistries were calculated. In conditions without LD, the overall incidence were 0.54 (95%CI 0.20-1.17) per 1000 person-months for ALT⩾3xULN, 0.36 (95%CI 0.10-0.92) for ALT⩾5xULN, and 0.27 (95%CI 0.06-0.78) for ALT⩾8xULN, 1.03 (95%CI 0.50-1.90) for ALP⩾2xULN, and 0.22 (95%CI 0.03-0.78) for combined ALT⩾3xULN and TBIL⩾2xULN. Incidence of ALT⩾3xULN (8.17 95%CI 6.42-10.24) were much higher in trials of conditions with LD. However, combined elevations of ALT⩾3xULN and TBIL⩾2xULN were only marginally higher 0.37 (95%CI 0.10-1.08). Elevations of ALT (3xULN) and TBIL (2xULN) are rare in pediatric trial populations for conditions without underlying liver disease and can be considered a safety signal. For trials in conditions with liver disease, the potential for drug-induced liver injury must be distinguished from underlying disease progression.
    Regulatory Toxicology and Pharmacology 10/2011; 62(2):329-35. · 2.13 Impact Factor
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    ABSTRACT: This study aimed to investigate the evolution of treatment within patients with newly diagnosed epilepsy identified from a large US commercial health care database. Postdiagnosis, patient follow-up was divided into observation units defined by consecutive antiepileptic drug (AED) prescriptions. Consecutive prescriptions were compared to assess whether a change in AED regimen had occurred. Factors associated with a regimen change were explored using a logistic regression model with subject random effects. Among 5930 patients with newly diagnosed epilepsy, there was a median of one regimen change in the first year. However, patients prescribed polytherapy regimens early in the course of disease were at a substantially greater risk of a regimen change (polytherapy vs monotherapy odds ratio=10.2, 95% confidence interval=9.2-11.3). Although a seizure during the preceding 90 days significantly increased the risk of a regimen change, it was beyond the scope of the study to determine the proportion of changes directly attributable to uncontrolled seizures.
    Epilepsy & Behavior 06/2011; 21(2):168-72. · 1.84 Impact Factor
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    ABSTRACT: To explore differential prescribing of anti-epileptic drugs (AEDs) to patients with epilepsy by history of mood disorder. Epilepsy was defined as at least one diagnosis code and one AED prescription, and all patients must have been on the database 182 days before and after their first AED prescription. The Integrated HealthCare Information Services (IHCIS) insurance claims database included 44 557 patients with epilepsy between January 1997 and March 2007. The General Practice Research Database (GPRD) included 16 904 patients with epilepsy up to March 2007. Patients were categorized by their first use of specified AEDs. Mood disorders were defined as diagnosis codes for depression and bipolar disorder, or anti-depressant use. The unadjusted odds ratios and 95% confidence intervals for a history of mood disorder diagnosis ever or within the three months prior to AED use were calculated with carbamazepine and oxcarbazepine (CBZ) as the referent. In the US IHCIS, a history of mood disorders was significantly more common in new users of most AEDs compared to CBZ new users, indicating differential prescribing. Clonazepam and gabapentin were the most commonly prescribed AEDs in patients with epilepsy and a history of mood disorders.In the UK GPRD, there was less evidence of differential prescribing of AEDs, although gabapentin was prescribed most often to epilepsy patients with a history of mood disorders. Any observational studies of AEDs and suicidality would have to consider potential channeling bias by history of mood disorders, which is a major risk factor for suicide.
    Pharmacoepidemiology and Drug Safety 03/2010; 19(3):289-95. · 2.90 Impact Factor
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    ABSTRACT: One limitation of neuropathic pain clinical trials is the often large and variable extent of response in the placebo group, possibly obscuring true medication effects. We pooled data from 252 individuals in the placebo arms of 3 clinical trials of lamotrigine in patients with neuropathic pain to examine the relationship of baseline patient and study site characteristics with 12-week change in the Pain Intensity Numerical Rating Scale score (DeltaPI-NRS). The 574 patients in the pooled lamotrigine treatment arms were used as a replication dataset. We performed univariable and multivariable regression analysis of predictors of DeltaPI-NRS. Clinical factors examined were baseline pain intensity score (mean daily PI-NRS over the week prior to randomization), age, sex, diagnosis, prior and concurrent gabapentin use, prior and concurrent tricyclic antidepressant use, pain duration, variability of daily pain scores during the baseline week, and slope of daily pain scores over the baseline week. Site factors evaluated were study site, US geographic region, recruitment rate, and recruitment period. Baseline PI-NRS and site recruitment rate were independent predictors of the 12-week DeltaPI-NRS in the last observation carried forward, observed case, and repeated measures analyses. Patients with higher baseline PI-NRS scores had a significantly greater 12-week reduction in pain intensity than patients with lower baseline scores. Patients within sites with a faster recruitment rate also had a significantly greater reduction of pain intensity than those in sites with slower recruitment. These results suggest that both patient and study site characteristics can influence the response in the placebo arms of neuropathic pain studies.
    The Clinical journal of pain 01/2009; 25(6):469-76. · 3.01 Impact Factor
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    ABSTRACT: One limitation of several recent 24 week Alzheimer's disease (AD) clinical trials was the lack of cognitive decline detected by the AD Assessment Scale-cognitive subscale (ADAS-cog) in the placebo groups, possibly obscuring true medication effects. Data from 733 individuals in the placebo arms of six AD clinical trials performed 1996-1997 were pooled to examine the relationship of clinical, demographic, and genetic characteristics with the 24 week change in ADAS-cog. Baseline cognitive and functional status and the screening-to-baseline change in ADAS-cog were the strongest independent predictors of the 24 week change in ADAS-cog. The ADAS-cog did not detect progression in patients with mild dementia (screening Mini-Mental State Exam, MMSE, >or=20). The change in ADAS-cog from screening to baseline was inversely correlated with the 24 week change score; it was more difficult to detect cognitive decline at 24 weeks if individuals markedly worsened from screening to baseline. The effects of baseline MMSE and screening-to-baseline change in ADAS-cog generalized to the placebo group (N=106) of another AD study performed in 2004-2005. Overcoming lack of placebo decline in AD clinical trials will require scales more sensitive to cognitive decline in mild AD and strategies to reduce within-person variability in outcome measures.
    Journal of Alzheimer's disease: JAD 07/2008; 14(3):301-11. · 4.17 Impact Factor
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    ABSTRACT: Most previous observational studies assessing cardiovascular risk associated with Cox-2 inhibitors (Cox-2is) used a case control approach, limiting the assessment of absolute risk by disease group and effect of duration of exposure. We conducted a retrospective cohort study in patients with osteoarthritis. Using the Life-link US claims database, all subjects had at least five years history in the database. Exposure was defined as the first chronic period of Cox-2i (celecoxib, rofecoxib or valdecoxib) or naproxen use. Non-users and non-chronic users of non-steroidal anti-inflammatory drug (NSAID)/Cox-2i within the osteoarthritis cohort served as the reference. The primary outcome was myocardial infarction and ischaemic stroke. A cohort of 16,580 subjects were chronically exposed to celecoxib, 9800 received rofecoxib, 2907 received naproxen and 51,539 were non-chronically exposed controls. With a median follow up of 506 days, there were 2116 ischaemic events for the entire cohort. The strongest predictors of AMI/ ischaemic stroke risk were history of ischaemic stroke (HR 2.34, 2.12-2.59) and age 65+ years (HR 2.28, 2.07-2.52). For rofecoxib, (HR 1.25,1.04-1.50), the attributable risk varied from 3 per 1000 patients years in individuals aged under 65 years with no history of CVD to 19 per 1000 patients years in older individuals with a history of CVD. The hazard ratios did not change over time. Celecoxib and naproxen were not associated with increased risks. The attributable risk for rofecoxib varied substantially with the underlying cardiovascular risk profile, being lower in clinical trial than in clinical practice populations.
    Pharmacoepidemiology and Drug Safety 07/2008; 17(6):601-8. · 2.90 Impact Factor
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    ABSTRACT: To study the association between use of antiepileptic drugs (AEDs) and risk of fractures. The authors obtained data from the General Practice Research Database (GPRD). A case-control study was nested within a cohort of patients with active epilepsy. Cases were patients with a first fracture after cohort entry. Up to four controls were matched to each case by practice, sex, year of birth, timing of first epilepsy diagnosis, index date, and duration of GPRD history. Cumulative exposure to AEDs was assessed by summing the duration of all AED prescriptions. A distinction was made between AEDs that induce the hepatic cytochrome P-450 enzyme system and AEDs that do not. Medical conditions and drugs known to be associated with bone metabolism or falls were evaluated as potential confounders. Conditional logistic regression analysis was used to calculate odds ratios (ORs) and 95% CIs. The study population comprised 1,018 cases and 1,842 matched controls. The risk of fractures increased with cumulative duration of exposure (p for trend < 0.001), with the strongest association for greater than 12 years of use: adjusted OR 4.15 (95% CI 2.71 to 6.34). Risk estimates were higher in women than in men. There was no difference between users of AEDs that induce and AEDs that do not induce the hepatic cytochrome P-450 system. Long-term use of AEDs was associated with an increased risk of fractures, especially in women. More research on mechanisms of AED-induced bone breakdown and female vulnerability to the effects of AEDs on bone health is warranted.
    Neurology 06/2006; 66(9):1318-24. · 8.25 Impact Factor
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    ABSTRACT: To compare the incidence of various fractures in a cohort of patients with epilepsy with a reference cohort of patients not having epilepsy. Patients were included in the epilepsy cohort if they had at least one diagnosis of epilepsy in their medical history and had sufficient evidence of "active" epilepsy (use of antiepileptic drugs, diagnoses) after the practice was included in the General Practice Research Database (GPRD). Two reference patients were sampled for each patient with epilepsy from the same practice. Primary outcome was the occurrence of any fracture during follow-up. Poisson regression analysis was used to estimate incidence density ratios (IDRs). The study population comprised 40,485 and 80,970 patients in the epilepsy and reference cohorts, respectively. The median duration of follow-up was approximately 3 years. The overall incidence rate in the epilepsy cohort was 241.9 per 10,000 person-years. This rate was about twice as high as that in reference cohort: age- and sex-adjusted IDR, 1.89 (95% CI, 1.81-1.98). When comparing IDRs among the different groups of fractures, the highest relative-risk estimate was found for hip and femur fractures (adjusted IDR, 2.79; 95% CI, 2.41-3.24). IDRs were consistently elevated across age and sex groups and across fracture subtypes. The overall risk of fractures was nearly twice as high among patients with epilepsy compared with the general population. The relative fracture risk was highest for hip and femur. Further study is necessary to elucidate whether this elevated risk is due to the disease, the use of antiepileptic drugs, or both.
    Epilepsia 03/2005; 46(2):304-10. · 3.91 Impact Factor