Tami R. Argo

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

ABSTRACT: 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.

The association of weight gain and olanzapine plasma concentrations

Abstract: 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 (≥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 ≥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.

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, paliperidones 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.

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 agents 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 patients 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.

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.

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.