Association between topiramate use and serum bicarbonate levels in a veteran population.

BACKGROUND: Topiramate has been associated with metabolic acidosis secondary to decreased serum bicarbonate. Product labeling recommends serum bicarbonate monitoring at baseline and periodically thereafter. OBJECTIVE: The study objective was to assess changes in serum bicarbonate within the first year of topiramate use in an outpatient veteran population. METHODS: This was a single-center, retrospective study conducted at the Iowa City Veterans Affairs Health Care System. Inclusion criteria required a minimum of 1 topiramate outpatient prescription between October 1, 1999, and August 31, 2012, and at least 1 serum bicarbonate level within 12 months prior to topiramate initiation. Patients with topiramate nonadherence, concurrent use of sodium bicarbonate or oral carbonic anhydrase inhibitors, and individual serum bicarbonate values obtained during inpatient hospitalizations were excluded. Change in bicarbonate was evaluated using a paired t test. Decreases in bicarbonate of ≥5 mEq/L, values <20 mEq/L, days to lowest value, and correlation between adverse drug reactions (ADRs) and topiramate discontinuation were evaluated. RESULTS: Of 546 patients reviewed, 350 were included in the analysis. There was a statistically significant decrease of 2.7 mEq/L in bicarbonate following initiation of topiramate. Only 1 patient had a bicarbonate value <17 mEq/L. There was no association between bicarbonate decrease ≥5 mEq/L and ADRs. CONCLUSIONS: A statistically significant reduction in bicarbonate levels occurred with topiramate, which was clinically insignificant. ADR occurrence did not correlate with bicarbonate levels <17 mEq/L or a decrease ≥5 mEq/L. Our results indicate that serum bicarbonate levels should only be monitored before topiramate initiation and in patients presenting with symptoms suggestive of acidosis.

The impact of posttraumatic stress disorder on blood pressure and heart rate in a veteran population.

Hyperarousal is a hallmark of posttraumatic stress disorder (PTSD). PTSD has been associated with increased blood pressure (BP) and heart rate (HR) in veteran populations. We retrospectively identified male patients consulted to outpatient psychiatry at the Iowa City Veterans Affairs Healthcare System. Patients were divided into PTSD (n = 88) and non-PTSD (n = 98) groups. All PTSD patients and a subset of non-PTSD patients had documented blast exposure during service. The study investigated whether patients with PTSD had higher systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) than patients without PTSD. The effect of trauma exposure on BP was also examined. Mean SBP (133.8 vs. 122.3 mm Hg; p < .001), DBP (87.6 vs. 78.6 mm Hg; p < .001), and HR (78.9 vs. 73.1 bpm; p < .001) were all significantly higher in the PTSD group. Trauma-exposed patients without PTSD had significantly higher BP than nonexposed patients. The prevalence of hypertension (HTN) was 34.1% (diagnosed and undiagnosed) among PTSD patients. Patients with PTSD had higher BP and HR compared to patients without PTSD. Trauma exposure may increase BP in this population. These findings will increase awareness about the cardiovascular implications of PTSD.

Adverse neuropsychiatric events associated with varenicline use in veterans: a case series.

Varenicline represents a major advance in the treatment of nicotine addiction and has been shown to be safe and effective to promote abstinence. However, in a small number of patients, neuropsychiatric adverse events and worsening of underlying psychiatric conditions have been reported. As the veteran population has higher rates of co-morbid psychiatric conditions and nicotine dependence this population may be at higher risk for serious adverse effects to varenicline warranting close monitoring. Herein we report seven cases of varenicline associated neuropsychiatric adverse events and describe an institutional response to adequately monitor patients to ensure safety and efficacy.

Diabetes prevalence estimates in schizophrenia and risk factor assessment.

BACKGROUND: Atypical antipsychotics have been indirectly associated with the diagnosis of type 2 diabetes mellitus (T2DM) in patients with schizophrenia. The purpose of this cross-sectional study was to determine the prevalence of T2DM and to examine the risk factors associated with T2DM among outpatients diagnosed with schizophrenia. The study also sought to determine which risk factors are of particular screening importance in monitoring the metabolic status of these patients. METHODS: This study included 202 patients diagnosed with schizophrenia. Data on a number of known and hypothesized risk factors for T2DM were collected. RESULTS: Risk factors for T2DM identified by bivariate analyses in this sample included older age, waist-to-hip ratio >1.0, sedentary lifestyle, number of hours worked per week, hyperlipidemia, previous screening for T2DM, higher random blood glucose, and number of years on atypical antipsychotics risperidone or olanzapine. However, further scrutiny using multiple logistic regression identified only sedentary lifestyle, waist-to-hip ratio ≥1.0, and a diagnosis of hyperlipidemia as significant risk factors in these patients. Similar to other studies, there was an 11.5% (22/192) lifetime prevalence rate of diabetes among this population. CONCLUSIONS: Risk factors traditionally associated with T2DM, as well as waist-to-hip ratio, are the factors most strongly associated with increased risk of diabetes in patients with schizophrenia.

Prazosin Outcomes in Older Veterans With Posttraumatic Stress Disorder.

Even at relatively high dosages, prazosin was well tolerated and significantly improved posttraumatic stress disorder severity and related nightmares in an older patient population.

The use of psychotropic medication for children in foster care.

The use of psychotropic medication for foster children is in itself not unique; however, these children are of particular interest because of the stress associated with their life situations. A thorough assessment of the child and family should occur before beginning these medications, and in general, they should only be used in the presence of a Diagnostic and Statistical Manual, 4th edition, diagnosis of a mental disorder. Parents and caregivers need to be aware of principles of use, potential side effects, and monitoring parameters.

Prazosin initiation and dose titration in a patient with posttraumatic stress disorder on concurrent carvedilol.

One mechanism involved in the pathophysiology of posttraumatic stress disorder (PTSD) is increased noradrenergic stimulation. Prazosin, a commonly utilized treatment for PTSD nightmares, works to block noradrenergic stimulation of the alpha-1 adrenoreceptor. Dual antagonism of this receptor would be expected to increase risk of adverse effects. Carvedilol has both alpha-1 adrenergic and nonselective beta-adrenoreceptor antagonist activity. To our knowledge, there is no clinical guidance on use of prazosin in patients concomitantly prescribed carvedilol for hypertension. This case describes the successful titration of prazosin for PTSD symptoms in a 49-year-old male concurrently prescribed carvedilol for hypertension. This patient had a previous unsuccessful prazosin trial due to adverse effects. His second trial of prazosin was efficacious and well tolerated using individualized titration with close monitoring by mental health clinical pharmacy specialists in the pharmacist-managed prazosin titration clinic. This case details the importance of utilizing caution and close follow-up in prazosin dose titration in patients prescribed concomitant alpha-1 antagonists. This appears to be the first case report describing the successful dose titration of prazosin for PTSD in a patient on a concurrent alpha-1 antagonist antihypertensive agent.

Attitudes Toward Medications and the Relationship to Outcomes in Patients with Schizophrenia.

The determinants of attitudes toward medication (ATM) are not well elucidated. In particular, literature remains equivocal regarding the influence of cognition, adverse events, and psychiatric symptomatology. This study evaluated relationships between those outcomes in schizophrenia and ATM. This is a retrospective analysis of data collected during the Texas Medication Algorithm Project (TMAP, n=307 with schizophrenia-related diagnoses), in outpatient clinics at baseline and every 3 months for ≥1 year (for cognition: 3rd and 9th month only). The Drug Attitude Inventory (DAI-30) measured ATM, and independent variables were: cognition (Trail Making Test [TMT], Verbal Fluency Test, Hopkins Verbal Learning Test), adverse events (Systematic Assessment for Treatment-Emergent Adverse Events, Barnes Akathisia Rating Scale), psychiatric symptomatology (Brief Psychiatric Rating Scale, Scale for Assessment of Negative Symptoms [SANS]), and medication adherence (Medication Compliance Scale). Analyses included binary logistic regression (cognition, psychiatric symptoms) and chi-square (adverse events, adherence) for baseline comparisons, and linear regression (cognition) or ANOVA (adverse events, adherence) for changes over time. Mean DAI-30 scores did not change over 12 months. Odds of positive ATM increased with higher TMT Part B scores (p=0.03) and lower SANS scores (p=0.02). Worsening of general psychopathology (p<0.001), positive symptoms (p<0.001), and negative symptoms (p=0.007) correlated with negative changes in DAI-30 scores. Relationships between cognition, negative symptoms, and ATM warrant further investigation. Studies evaluating therapies for cognitive deficits and negative symptoms should consider including ATM measures as endpoints. Patterns and inconsistencies in findings across studies raise questions about whether some factors thought to influence ATM have nonlinear relationships.

The association of alcohol-induced blackouts and grayouts to blood alcohol concentrations.

The primary aim of this study was to investigate the association between measured blood alcohol concentration (BAC) and the presence and degree of amnesia (no amnesia, grayout, or blackout) in actively drinking subjects. A secondary aim was to determine potential factors other than BAC that contribute to the alcohol-induced memory loss. An interview questionnaire was administered to subjects regarding a recent alcohol associated arrest with a documented BAC greater than 0.08 g/dL for either public intoxication, driving under the influence, or under age drinking was administered. Demographic variables collected included drinking history, family history of alcoholism, presence of previous alcohol-related memory loss during a drinking episode, and drinking behavior during the episode. Memory of the drinking episode was evaluated to determine if either an alcohol-induced grayout (partial anterograde amnesia) or blackout (complete anterograde amnesia) occurred. Differences in (1) mean total number of drinks ingested before arrest, (2) gulping of drinks, and (3) BAC at arrest were found for those having blackouts compared with no amnesia; while differences in drinking more than planned were found between the no amnesia and grayout groups. A strong linear relationship between BAC and predicted probability of memory loss, particularly for blackouts was obvious. This finding clinically concludes that subjects with BAC of 310 g/dL or greater have a 0.50 or greater probability of having an alcoholic blackout.

Effect of selected clinical trial publication on adjunctive nonstatin medication prescribing in the Veterans Health Administration system.

PURPOSE: The question of whether publication of selected clinical trials is temporally followed by changes in prescribing of adjunctive lipid-lowering medications was evaluated. METHODS: In this retrospective preanalysis and postanalysis, Veterans Health Administration (VHA) patients 18 years or older who received a new or renewed order for any lipid-lowering medication between April 2, 2004, and September 2, 2014, were included. This period was chosen based on the publication dates of three trials investigating the efficacy of nonstatin medications: Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia (ENHANCE, April 3, 2008), Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus (ACCORD Lipid, March 14, 2010), and Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy (AIM-HIGH, December 15, 2011). Annual prescribing rates for ezetimibe, fibrates, and niacin were analyzed for 4 years before and after the ENHANCE, ACCORD, and AIM-HIGH trial publication dates, respectively (3 years for niacin in AIM-HIGH) and reported as percent of patients in the cohort. RESULTS: Among patients receiving lipid-lowering medications, relatively low overall prescribing rates were observed for all three target medications. Prescribing rates for each medication decreased after its respective trial publication, with ezetimibe having the greatest change. CONCLUSION: Prescribing of fibrates, niacin, and ezetimibe in the VHA system decreased after the publication of landmark trials assessing their addition to a statin, consistent with the recommendations in the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline, which did not encourage routine use of adjunctive therapies to lower the risk of cardiovascular disease.

Exacerbation of panic disorder with rifampin therapy in a patient receiving citalopram.

Citalopram, a selective serotonin reuptake inhibitor, is used in the management of anxiety disorders. A 55-year-old man receiving citalopram for panic disorder reported a decrease in the agent's therapeutic efficacy when rifampin was started for osteomyelitis. His condition improved when the rifampin was stopped. Rifampin is known to induce the metabolism of cytochrome P450 3A4 substrates and thus plays a role in several drug-drug interactions. We suspect that the efficacy of citalopram was blunted with the concurrent use of rifampin. To our knowledge, only one other case of an interaction of rifampin with a selective serotonin reuptake inhibitor is described in the literature. Clinicians should monitor all drugs and dietary supplements that patients with psychiatric conditions take, regardless of the indication, intended purpose, or prescriber. This is especially important, however, for a drug that is pivotal to a patient's well-being; its therapeutic effect should be carefully monitored when any new drug is added or a change in the dosage of a concurrent drug is made.

Aripiprazole, a novel atypical antipsychotic drug.

Before the 1990s, treatment of psychoses centered on conventional agents whose tolerability was limited by extrapyramidal side effects (EPS). The past decade has seen the emergence of a newer generation of antipsychotic agents, first with clozapine and followed shortly by risperidone, olanzapine, quetiapine, and ziprasidone. These agents have been touted as providing better negative symptom efficacy, less impaired cognition, and lower risk of extrapyramidal syndromes. However, evolving evidence suggests that several drugs in this class may be associated with significant weight gain and lipid abnormalities. Aripiprazole, a new atypical antipsychotic drug, displayed efficacy similar to that of haloperidol and risperidone and superior to that of placebo in numerous clinical trials. Aripiprazole does not cause significant prolactin elevation and is associated with a low rate of clinically significant weight gain compared with other atypical antipsychotics. Patients receiving aripiprazole experienced EPS at a rate similar to that seen with placebo. Aripiprazole provides a new treatment option with limited adverse effects for patients in need of antipsychotic therapy.

Paliperidone extended-release tablets for the acute and maintenance treatment of schizophrenia.

BACKGROUND: Paliperidone, which is available in extended-release (ER) tablets, was approved by the US Food and Drug Administration in 2007 for the acute and maintenance treatment of schizophrenia. It is the seventh second-generation antipsychotic (SGA) to be introduced to the US market. Paliperidone is the major active metabolite of risperidone, an established anti-psychotic agent. OBJECTIVE: This article reviews the available literature on the pharmacodynamics, pharmacokinetics, clinical efficacy, and tolerability of paliperidone. METHODS: A comprehensive search of MEDLINE using the terms paliperidone, 9-hydroxy-risperidone, and Invega was performed for the years 1950 through December 2007. Articles that discussed the efficacy and tolerability of 9-hydroxy-risperidone formed as a metabolite of risperidone were excluded; all others were included. Abstracts and posters presented at recent national and international scientific meetings were also included in the review. RESULTS: At therapeutic doses (3-12 mg), paliperidone ER follows linear pharmacokinetics. Like that of its parent drug, paliperidone's mechanism of action is thought to be through antagonistic actions at dopamine D(2) and serotonin-2A receptors. In vivo studies suggest that the cytochrome P450 enzyme system plays a minimal role in paliperidone metabolism, with none of the metabolites accounting for >10% of a dose. The majority (59%) of paliperidone is eliminated through the kidneys as unchanged drug. The results of three 6-week, randomized, double-blind, parallel-group trials indicated the efficacy of paliperidone ER compared with placebo in the treatment of acute exacerbations of schizophrenia, with response rates ranging from 39.8% to 61.0% for paliperidone ER, compared with 18.3% to 34.0% for placebo. During a 52-week, double-blind, relapse-prevention trial, the time to 25% of patients experiencing a recurrence was 83 days for paliperidone ER, compared with 23 days for placebo. The proportions of patients in the 6-week trials who reported at least 1 extrapyramidal symptom-related adverse event were 13%, 10%, 25%, 26%, and 24% for paliperidone ER 3, 6, 9, 12, and 15 mg/d, respectively; the pooled incidence rate was not statistically different from that with placebo (11%). Headache and insomnia were the most common adverse events in patients treated with paliperidone ER in the 6-week trials (pooled data: 11%-18% and 4%-14%, respectively). In the relapse-prevention trial, the incidence of prolactin-related adverse events was 4% for paliperidone ER and 0% for placebo. CONCLUSIONS: Current evidence supports the efficacy and tolerability of paliperidone ER in the acute and long-term treatment of schizophrenia. Randomized, head-to-head comparisons with other SGAs, particularly risperidone, are needed to define the role of paliperidone ER in the treatment of schizophrenia.

Bupropion in the treatment of pathological gambling: a randomized, double-blind, placebo-controlled, flexible-dose study.

We tested the efficacy of bupropion in the treatment of persons with pathological gambling (PG). Nondepressed, healthy subjects with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition PG were randomly assigned to placebo or flexibly dosed bupropion in a 12-week double-blind trial. Outcome measures included the Yale-Brown Obsessive-Compulsive Scale modified for PG, the Gambling Severity Assessment Scale, the Clinical Global Impression Improvement and Severity Scales, the Global Assessment Scale, the Timeline Follow Back, the Attention-Deficit/Hyperactivity Disorder Rating Scale, and the Sheehan Disability Scale. Thirty-nine subjects (28 men, 11 women) were randomized to bupropion (n = 18) or placebo (n = 21). The 2 groups were similar on demographic and clinical measures. There were few differences between the treatment groups on any primary or secondary outcome measure, although subjects in each cell experienced significant improvement. Of subjects with at least 1 postrandomization visit, 35.7% of bupropion and 47.1% of placebo recipients experienced "much" or "very much" improvement on the Clinical Global Impression Improvement Scale. The trial was complicated by a high noncompletion rate (43.6%). Bupropion was well tolerated. Bupropion and placebo recipients did equally well in a short-term trial, with improvement seen as early as the first week of treatment. The high placebo response rate and the high noncompletion rate each reflect the challenge inherent in treating persons with PG.

A regional comparison of developing diabetes among VA patients exposed to typical and atypical antipsychotics relative to corticosteroids and proton pump inhibitors.

BACKGROUND: Metabolic changes, including weight gain and onset of diabetes, have been associated with both systemic corticosteroid use and atypical antipsychotic drugs. The purpose of this study was to quantify and compare the risk of new-onset diabetes mellitus in a Veterans Affairs population receiving antipsychotics and corticosteroids, using persons taking proton pump inhibitors as a control group. METHODS: This study included data from subjects treated within Veterans Integrated Service Network 23 who had received an outpatient prescription in fiscal years (FY) 1999 or 2000 for a corticosteroid (CS), a proton pump inhibitor (PPI), a typical antipsychotic, or an atypical antipsychotic. Patients receiving prescriptions in more than one class were not excluded. Subjects were excluded if they had a documented diagnosis of diabetes either in the previous FY year (1998) or prior to their index prescription date. RESULTS: Thirteen percent of the population had a new diagnosis for diabetes during the two-year study. Cox-regression analysis using time dependent covariates determined a significantly higher risk of developing diabetes (RR = 1.21) in users of CS relative to PPIs. Demographic variables including age, race, gender, marital status, and VA financial classification as well as a marker for schizophrenia, were also included in the model. Comparison of both typical and atypical antipsychotics to PPIs found an increased but nonsignificant risk of developing diabetes (RR = 1.18 and RR = 1.19 respectively). CONCLUSIONS: The diabetogenic risk associated with atypical antipsychotics was found to be less than that of corticosteroids when compared to controls. Periodic monitoring of blood glucose should be considered with chronic use of an agent from either class.

The association of weight gain and olanzapine plasma concentrations.

Atypical antipsychotics, including olanzapine, have been associated with clinically significant weight gain in some patients. The purpose of this study was to determine if weight gain was associated with increasing plasma concentrations during olanzapine treatment in subjects with schizophrenia. This study included 39 acutely ill subjects with schizophrenia, schizoaffective disorder, or schizophreniform disorder (DSM-III-R or DSM-IV). Assessments included the Brief Psychiatric Rating Scale (BPRS), the Scale for Assessment of Negative Symptoms (SANS), and weight measurements. Olanzapine was titrated to a dose of 5 to 20 mg/d for 2 to 6 weeks. A 24-hour plasma concentration was obtained after 6 weeks of treatment. Analysis using a receiver operator characteristic curve identified a threshold dose-weighted plasma concentration of 20.6 ng/mL being associated with an increased likelihood of clinically significant weight gain (> or =7% baseline weight) during olanzapine treatment. The associations remained significant after adjusting for age, gender, baseline body mass index, baseline symptom severity, and symptom improvement (OR = 10.1; 95% CI, 1.3-75.0; P = 0.024). Similar analysis determined that a threshold olanzapine dose of 13.3 mg/d was associated with > or =7% weight gain. However, after adjusting for potential confounders, the results did not remain significant. The association of weight gain with plasma concentrations during treatment with olanzapine may support the utilization of plasma drug concentration as a marker for antipsychotic-induced weight gain in the treatment of schizophrenia.