Nick C. Patel

Risk of Cerebrovascular Events Associated with Antidepressant Use in Patients with Depression: A Population-Based, Nested Case-Control Study:

Background: Given the widespread use of antidepressants and the negative consequence of cerebrovascular events (CVEs), an evaluation of the risk of CVEs associated with antidepressants is warranted. Objective: To examine the association between the use of an antidepressant and risk of CVEs among patients diagnosed with depression. Methods: A case-control study was performed using a managed care medical claims database from 1998 through 2002. A total of 1086 cases with CVEs were identified and matched with 6515 controls by age, sex, and the year ol the index date of depression Case patients were categorized by stroke type: hemorrhagic stroke, ischemic stroke, and other CVEs. Diagnoses of depression, CVEs, and other medical comorbidities were identified based on International Classification of Diseases, Ninth Revision, codes. Patients were defined as current users (antidepressant ended ≤30 days before CVE). recent users (31–60 days before CVE), past users {61–90 days before CVE), and remote/nonusers (≥91 days before CVE or nonuse). Cox proportional hazards regression analysis was conducted to estimate the risk of CVEs associated with antidepressant use. Results: A 24% increased risk of a CVE was noted in patients with current exposure to selective serotonin-reuptake inhibitors (SSRIs; adjusted hazard ratio [HR) 1.24; 95% CI 1.07 to 1.44), 34% increased risk for current exposure to tricyclic antidepressants (HR 1.34; 95% CI 1.10 to 1.62), and 43% increased risk for current exposure toother antidepressants (HR 1.43; 95% CI 1.21 to 1.69). The risk of ischemic stroke in current SSRI users was significantly higher (HR 1.55; 95% CI 1.00 to 2.39) compared with remote/nonusers. Conclusions: Current users of antidepressants may be at increased risk of a CVE. Clinicians should consider the relationship of antidepressants with the occurrence of CVEs when determining the risk-benefit profile of pharmacologic treatment in patients with depression, particularly those with existing risk factors for a CVE.

Temporal Change in N-Acetyl-Aspartate Concentrations in Adolescents with Bipolar Depression Treated with Lithium

OBJECTIVEnThis proton magnetic resonance spectroscopy (1H MRS) study identified the in vivo effects of lithium on N-acetyl-aspartate (NAA) concentrations in adolescent bipolar depression.nnnMETHODnTwenty eight adolescents with bipolar I disorder in a depressive episode received open-label lithium 30 mg/kg, adjusted to achieve serum levels of 1.0-1.2 mEq/L. Medial ventral and ventral lateral prefrontal NAA concentrations were measured at baseline, day 7, and day 42 of treatment. Temporal changes in NAA concentrations were analyzed and effect sizes (Cohens d) were calculated.nnnRESULTSnMedial ventral prefrontal NAA concentrations decreased over time (p = 0.03), with day-42 concentrations significantly lower than baseline concentrations (p = 0.01, d = 0.7). No significant time effects on NAA concentrations were observed in the left (p = 0.2) or right ventral lateral (p = 0.3) prefrontal cortices.nnnCONCLUSIONSnIn contrast with prior studies of bipolar adults, this study observes that ventral prefrontal NAA concentrations do not significantly increase from baseline following lithium treatment in adolescent bipolar depression. The results should be viewed in the context of the studys limitations, including the lack of a matched healthy control group. Additional longitudinal magnetic resonance imaging studies are warranted to understand better the role of NAA in the pathophysiology of bipolar disorder and neurochemical mechanisms by which lithium stabilizes mood.

Atypical neuroleptic malignant syndrome: diagnostic controversies and considerations.

Neuroleptic malignant syndrome (NMS) is a serious and potentially fatal adverse effect of antipsychotic drugs. The diagnosis of NMS commonly requires core symptoms of hyperthermia and muscle rigidity. Although diagnostic criteria for NMS have been established and are widely accepted and used, it should be recognized that atypical presentations pose a diagnostic dilemma, as hyperthermia and/or muscle rigidity may be absent or develop slowly over several days, leading to impairment or a significant delay in diagnosis and treatment. Evidence from case reports and retrospective evaluations supports a concept of atypical NMS, particularly with regard to treatment with atypical antipsychotics. However, it remains unclear whether these atypical presentations represent early or impending NMS. Furthermore, it is unclear whether dysfunction in other neurotransmitter systems, in addition to dopamine, may be involved in the pathogenesis of NMS induced by atypical antipsychotics. In patients receiving any antipsychotic, clinicians should carefully evaluate any features of NMS and should not prematurely exclude a diagnosis of NMS in cases where severe rigidity or hyperthermia is not initially apparent.

Neurochemical Alterations in Adolescent Bipolar Depression: A Proton Magnetic Resonance Spectroscopy Pilot Study of the Prefrontal Cortex

OBJECTIVEnIdentifying neurochemical alterations in adolescent bipolar depression may enhance our understanding of the neurophysiology of bipolar disorder across the age spectrum. The objective of this study was to compare in vivo neurometabolite concentrations in bipolar adolescents with a depressed episode and healthy adolescents using proton magnetic resonance spectroscopy ((1)H MRS).nnnMETHODnBipolar adolescents with a depressed episode (n = 28) and healthy adolescents (n = 10) underwent a (1)H MRS scan. Anterior cingulate (ACC) and left and right ventral lateral prefrontal (LVLPFC, RVLPFC) metabolite concentrations were calculated and compared between groups using analysis of covariance (ANCOVA).nnnRESULTSnANCOVA showed significant group differences in ACC N-acetyl-aspartate (NAA) (F(1,33) = 17.8, p = 0.0002), LVLPFC choline (Cho) (F(1,32) = 13.1, p = 0.001), creatine/phosphocreatine (Cr) (F(1,32) = 18.5, p = 0.0002), and NAA (F(1,32) = 13.6, p = 0.0008), and RVLPFC Cr (F(1,32) = 9.6, p = 0.004), mI (F(1,32) = 11.1, p = 0.002), and NAA (F(1,32) = 11.4, p = 0.002) concentrations. In general, the bipolar depressed group had higher neurometabolite concentrations than the healthy group.nnnCONCLUSIONSnThere may be localized alterations in brain neurometabolites in adolescents with bipolar depression. Limitations include lack of bipolar adolescents in other mood states and potential confounding effects of prior psychotropic medication use. Confirmatory (1)H MRS studies in larger samples of youths with bipolar depression are needed.

Risk of Hepatotoxicity Associated with the Use of Telithromycin: A Signal Detection Using Data Mining Algorithms

Background: With the exception of case reports, limited data are available regarding the risk of hepatotoxicity associated with the use of telithromycin. Objective: To detect the safety signal regarding the reporting of hepatotoxicity associated with the use of telithromycin using 4 commonly employed data mining algorithms (DMAs). Methods: Based on the Adverse Events Reporting System (AERS) database of the Food and Drug Administration, 4 DMAs, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the information component (IC), and the Gamma Poisson Shrinker (GPS), were applied to examine the association between the reporting of hepatotoxicity and the use of telithromycin. The study period was from the first quarter of 2004 to the second quarter of 2006. The reporting of hepatotoxicity was identified using the preferred terms indexed in the Medical Dictionary for Regulatory Activities. The drug name was used to identify reports regarding the use of telithromycin. Results: A total of 226 reports describing hepatotoxicity associated with the use of telithromycin were recorded in the AERS. A safety problem of telithromycin associated with increased reporting of hepatotoxicity was clearly detected by 4 algorithms as early as 2005, signaling the problem in the first quarter by the ROR and the IC, in the second quarter by the PRR, and in the fourth quarter by the GPS. Conclusions: A safety signal was indicated by the 4 DMAs suggesting an association between the reporting of hepatotoxicity and the use of telithromycin. Given the wide use of telithromycin and serious consequences of hepatotoxicity, clinicians should be cautious when selecting telithromycin for treatment of an infection. In addition, further observational studies are required to evaluate the utility of signal detection systems for early recognition of serious, life-threatening, low-frequency drug-induced adverse events.

Glutamatergic Effects of Divalproex in Adolescents With Mania: A Proton Magnetic Resonance Spectroscopy Study

OBJECTIVESnThis study used proton magnetic resonance spectroscopy ((1)H MRS) to evaluate the in vivo effects of extended-release divalproex sodium on the glutamatergic system in adolescents with bipolar disorder, and to identify baseline neurochemical predictors of clinical remission.nnnMETHODnAdolescents with bipolar disorder who were experiencing a manic or mixed episode (N = 25) were treated with open-label, extended-release divalproex (serum levels 85-125 μg/mL) and underwent (1)H MRS scanning at baseline (before treatment) and on days 7 and 28. Healthy comparison subjects (n = 15) also underwent (1)H MRS scanning at the same time points. Glutamate (Glu) and glutamate+glutamine (Glx) concentrations were measured in three voxels: anterior cingulate cortex (ACC), left ventrolateral prefrontal cortex (LVLPFC), and right ventrolateral prefrontal cortex (RVLPFC), and were compared between bipolar and healthy subjects. Within the bipolar subjects, Glu and Glx concentrations at baseline and each time point were also compared between remitters and nonremitters after divalproex treatment.nnnRESULTSnAt baseline, no differences in Glu or Glx concentrations between bipolar and healthy subjects were observed. Group (HC vs. BP) by time effects revealed an interaction for Glu in the ACC, and change over time effects for Glx were noted in the ACC in patients with bipolar disorder (increase from day 0 to day 7 and then a decrease from day 7 to day 28) but not in HC. Remitters had significantly lower baseline Glx concentrations in LVLPFC, and in remitters the change in LVLPFC Glu correlated with the change in YMRS score.nnnCONCLUSIONSnSuccessful treatment of mania with divalproex may be predicted by lower baseline concentrations of Glx in the LVLPFC. In addition, in remitters, the degree of symptomatic improvement is related to the change in Glu concentrations in this region, suggesting that divalproex may work via modulation of the prefrontal glutamatergic system in youth with bipolar disorder.

Hemorrhagic stroke associated with antidepressant use in patients with depression: does degree of serotonin reuptake inhibition matter?

This study aimed to determine whether the degree of serotonin (5‐HT) reuptake inhibition affects risk of hemorrhagic stroke associated with antidepressant use in patients with depression.

Pharmacist screening for depression among patients with diabetes in an urban primary care setting

OBJECTIVESnTo identify possible undiagnosed and undertreated depression in patients with diabetes in an urban primary care setting using screening by a student pharmacist, to develop a better understanding of the influence of comorbid depression on diabetes control, and to identify predictors of increased risk for comorbid depression.nnnMETHODSnPatients from an underserved, low-income, inner-city setting who were receiving primary follow-up diabetes care at five Cincinnati Health Department clinics were evaluated for depression using the Zung Self-rating Depression Scale (SDS). A student pharmacist questioned patients on their medical history and documented the information. After the appointment, the student pharmacist also gathered information from patient medical charts, including patient characteristics, age, social history, pertinent laboratory results (glycosylated hemoglobin [A1C], fasting blood glucose, lipid panel information), and documented comorbidities. A positive screen for depression was defined as an SDS score of 50 or more, and the result of the screening was documented as a clinical note in the patients medical chart. Based on SDS scores, severity of depressive symptoms was categorized as mild (50-59), moderate (60-69), or severe (> or = 70).nnnRESULTSn45 patients (2 with type 1 diabetes and 43 with type 2 diabetes, 41 aged > 40 years, 35 black, 31 women, and 31 uninsured) were enrolled in the study. Based on the data collected and SDS results, 12 patients (27%) had a current diagnosis of depression from their primary care physician. For this group of 12, the SDS acted as a quality-assurance tool, identifying 3 patients (25%) as adequately treated (SDS scores < 50), 6 (50%) as undertreated (SDS scores > or = 50 with pharmacologic and/or nonpharmacologic therapy), and 3 (25%) as not treated at all (SDS scores > or = 50 without pharmacologic or nonpharmacologic therapy). Of the 33 patients (73%) without a current diagnosis of depression, 16 (48%) screened positive for depression and 17 were not depressed (52%). No significant differences were observed between nondepressed and depressed participants in mean A1C or fasting blood glucose.nnnCONCLUSIONnPoorly controlled depression in patients with diabetes can be identified by pharmacists in the primary care setting via use of a brief screening tool such as the SDS.

Comparison of Sensitivity and Timing of Early Signal Detection of Four Frequently Used Signal Detection Methods

AbstractBackground: There are limited published comparative data regarding the sensitivity and timing of early signal detection with commonly used signal detection methods (SDMs), including the reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC) and gamma Poisson shrinker (GPS).n Objective: To examine the sensitivity and timing of early signal detection across four SDMs using the Adverse Events Reporting System (AERS) database of the US Food and Drug Administration.n Methods: The four SDMs were applied to retrospectively detect ten confirmed drug-event combinations (DECs). The sensitivity to detect adverse events was defined as the percentage of DECs detected by the respective SDMs as positive signals. The timing of early signal detection was measured by comparing the index date of withdrawal (IDW), defined as the date on which the drug was removed from the market, with the index date of detection (IDD), defined as a date on which the signal was significantly detected by the SDM.n Results: The estimated sensitivity was 100% for ROR, 90% for PRR and IC and 70% for GPS. The sensitivity increased with increasing numbers of reports per DEC. Compared with the IDW, the signals were detected on average 10 quarters earlier by ROR, 9 quarters earlier by PRR, 9.9 quarters earlier by the IC and 4.7 quarters earlier by GPS.n Conclusions: The sensitivity and timing of early signal detection varies across the four SDMs. Numerically, the ROR showed better performance in sensitivity and early signal detection based on ten selected DECs. Given the limited number and range of DECs selected in this study and the unavailability of specificity assessment, further large-scale prospective studies are warranted in order to provide better guidance on the selection of SDMs.

Risk of neuroleptic malignant syndrome in patients with bipolar disorder: a retrospective, population-based case-control study.

Introduction: Current data regarding risk factors of neuroleptic malignant syndrome (NMS) are limited. This study aims to examine factors associated with increased risk of NMS in patients with bipolar disorder. Methods: A retrospective, population-based, case-control study was performed using a medical claims database covering January 1998 to December 2002. Fifty cases with a diagnosis of NMS were identified and matched with 800 controls. Conditional logistic regression analysis was used to estimate crude and adjusted odds ratios (ORs) of risk of NMS. Results: Antipsychotic use was associated with an increased risk of NMS after controlling for other pharmacologic and clinical factors (OR = 2.36, 95% CI = 1.08–5.19). Other factors associated with an increased risk of NMS included being male (OR = 2.07, 95% CI = 1.07–4.02), confusion (OR = 2.91, 95% CI = 1.17–7.28), dehydration (OR = 3.99, 95% CI = 1.50–10.57), delirium (OR = 4.93, 95% CI = 2.07–11.72), and extrapyramidal symptoms (OR = 3.50, 95% CI = 1.10–11.09). Conclusions: Given the widespread use of antipsychotics for the treatment of bipolar disorder, clinicians should be vigilant of the potential pharmacologic and clinical factors associated with increased risk of NMS in patients with bipolar disorder.