Bruce Alexander

A Review of Carbamazepine's Hematologic Reactions and Monitoring Recommendations

Early case reports of fatal hematologic effects attributed to carbamazepine (CBZ) resulted in extensive monitoring recommendations by the manufacturer. The rarity of blood dyscrasias led many authors to question the manufacturers guidelines. Thus the manufacturer removed specific monitoring guidelines, allowing physicians to monitor CBZ using their clinical judgment. This article reviews case reports and studies of CBZs hematologic effects. Due to their rapid onset, daily laboratory checks would be necessary to monitor for aplastic anemia, agranulocytosis, and thrombocytopenia. These adverse effects are best monitored by informing patients and physicians to carefully watch for signs and symptoms. Leukopenia develops more slowly, occurring in approximately 12 percent of children and 7 percent of adults. Its onset is typically within the first three months of treatment, with patients at risk having a low or low-normal pretreatment white blood cell (WBC) count. Leukopenia often reverses, even if CBZ is continued. Based upon our review of the literature, we recommend monitoring of those high-risk patients during the first three months of treatment with the frequency being determined by results of each laboratory value. WBC counts <3000/mm3 or neutrophil counts below 1000/mm3 warrant a decrease in dose with frequent monitoring or CBZ discontinuation, if necessary.

Prescribing trends in veterans with posttraumatic stress disorder.

OBJECTIVE The revised Department of Veterans Affairs (VA) and Department of Defense Clinical Practice Guideline for Management of Post-Traumatic Stress recommends against long-term use of benzodiazepines to manage posttraumatic stress disorder (PTSD). An analysis of recent trends among veterans receiving care for PTSD in the VA noted a decreasing proportion receiving benzodiazepines. The authors examined prescribing patterns for other medications to better understand the general context in which the changes in benzodiazepine prescribing have occurred in the VA. METHOD Administrative VA data from fiscal years 1999 through 2009 were used to identify veterans with PTSD using ICD-9 codes extracted from inpatient discharges and outpatient encounters. Prescribing of antidepressants, antipsychotics, and hypnotics was determined for each fiscal year using prescription drug files. RESULTS The proportion of veterans receiving either of the 2 Clinical Practice Guideline-recommended first-line pharmacotherapy treatments for PTSD, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors, increased from 49.7% in 1999 to 58.9% in 2009. In addition to reduced benzodiazepine prescriptions, the overall frequency of antipsychotic use declined 6.1%, from 20.0% in 1999 to 13.9% in 2009. Nonbenzodiazepine hypnotic prescribing tripled when zolpidem was added to the VA national formulary in 2008. Buspirone prescribing decreased steadily, while prazosin prescribing expanded nearly 7-fold. CONCLUSIONS This work highlights several clinically important trends in prescribing over the past decade among veterans with PTSD that are generally consistent with the revised VA/Department of Defense Clinical Practice Guideline recommendations. However, the findings illustrate the limitations of administrative data and point to a need to supplement this work with a qualitative examination of PTSD prescribing from interviews with providers to better understand the strategies used to make medication management decisions.

Declining Benzodiazepine Use in Veterans With Posttraumatic Stress Disorder

OBJECTIVE Clinical practice guidelines issued by the US Department of Veterans Affairs (VA) and the Department of Defense caution against benzodiazepine use among veterans with posttraumatic stress disorder (PTSD) because of insufficient evidence for efficacy and emerging safety concerns. We examined recent trends in benzodiazepine prescribing among veterans with PTSD in terms of frequency of use, duration of use, and dose. METHOD Administrative VA data from fiscal years 1999 through 2009 were used to identify veterans with PTSD according to ICD-9 codes extracted from inpatient discharges and outpatient encounters. Benzodiazepine use among these individuals was determined for each fiscal year by using prescription drug files. Modal daily doses were examined by using standard daily dosage units. RESULTS The number of veterans receiving care for PTSD in the VA increased from 170,685 in 1999 to 498,081 in 2009. The proportion of individuals receiving a benzodiazepine decreased during this time period from 36.7% to 30.6%. In addition, the proportion of long-term users (> 90 days) decreased from 69.2% to 64.1%, and daily dose decreased from 2.1 to 1.8 standard daily dosage units. CONCLUSIONS Decreasing benzodiazepine use among veterans with PTSD is encouraging. However, the frequency of use remains above 30%, and focused interventions may be required to achieve further reductions. Given the growing number of veterans being diagnosed and treated for PTSD, minimizing benzodiazepine exposure will remain a vital policy issue for the VA.

Retrospective Study of Selegiline-Antidepressant Drug Interactions and a Review of the Literature

Selegiline is a selective monoamine oxidase inhibitor used in the treatment of Parkinsons disease. It is estimated that approximately one-half of Parkinsonian patients will develop depression requiring antidepressant drug treatment. Recently, selegilines package insert was revised to reflect the potential risk of adverse effects when it is used in combination with selective serotonin reuptake inhibitors and tricyclic antidepressants. The objective of our study is to assess the safety of combining selegiline with antidepressants. A retrospective chart review was performed on all 28 patients with Parkinsons disease receiving selegiline and antidepressants concurrently to identify possible drug interactions. Compliance was assessed according to prescription refill records. Suspected adverse reactions with combination therapy were documented. There was a total of 40 selegiline-antidepressant drug combinations involving tricyclic antidepressants (n = 25), selective serotonin reuptake inhibitors (n = 7), trazodone (n = 5), and bupropion (n = 3). One patient receiving fluoxetine developed a reaction consistent with the serotonin syndrome; however, it was never documented as such. No other selegiline drug interactions were found. Adverse effects noted were typical of antidepressant monotherapy. Although no selegiline drug interactions were documented in our study, the concurrent administration of selegiline and selective serotonin reuptake inhibitors should be avoided because of literature-reported interactions. We believe that bupropion, tricyclic antidepressants, and trazodone are reasonable choices in combination with selegiline, although tricyclic antidepressants and trazodone may be reserved as second-line treatments.

Sedative/hypnotic dependence: patient stabilization, tolerance testing, and withdrawal

Physical dependence to sedative/hypnotic drugs is not an uncommon clinical problem. The withdrawal syndrome is analogous to alcohol withdrawal, except the duration of the syndrome occurs over a longer period of time with the symptoms being less intense than generally encountered with alcohol. The potential for withdawal reactions is probably greater for the shorter-acting agents than the longer-acting drugs. Potentially dependent sedative/hypnotic users require stabilization of their symptoms initially, followed by tolerance testing. If tolerant, the patients should be withdrawn using either a long-acting sedative/hypnotic (e.g., diazepam) or phenobarbital. Compared to other benzodiazepines and barbiturates, diazepam appears to be the drug of choice for treating dependent patients. Diazepam is rapidly adsorbed and distributed to the brain and therefore useful for stabilization and tolerance testing. It is metabolized on chronic administration to a long-acting metabolite, desmethyldiazepam, which makes the drug ideal for a tapered withdrawal schedule.

Risk of mortality associated with antipsychotic and other neuropsychiatric drugs in pneumonia patients.

Objective: To evaluate the use of typical and atypical antipsychotic medications and associated in-hospital mortality in a group of Veterans Administration (VA) patients with pneumonia. Method: Our cohort consisted of 14,057 VA patients admitted for pneumonia in fiscal year (FY) 2003. Exposure to typical and atypical antipsychotics and other neuropsychiatric drugs was based on a prescription within 120 days preceding admission. Multivariate models determined the odds of mortality associated with each drug class and risk adjusted for comorbidity, admission source, demographic factors, and concurrent mental health conditions. The referent group for each analysis was pneumonia patients not receiving neuropsychiatric drugs. Results: In adjusted analyses, the odds of in-hospital mortality for VA patients admitted with pneumonia was higher for recent exposure to typical antipsychotics (OR = 1.51, 95% CI = 1.04 - 2.19; P = 0.03) when compared to patients not receiving neuropsychiatric medications. Patients exposed to atypical antipsychotics (OR = 1.20, 95% CI = 0.96 - 1.50, P = .10), tricyclic antidepressants (OR=1.20, 95% CI = 0.44 - 1.55; P = 0.15), other antidepressants (OR = 1.07, 95% CI = 0.93-1.23; P = 0.37), or mood stabilizers (OR=0.91, 95% CI= 0.73 - 1.14; P = 0.41) had no significant difference in in-hospital mortality. Conclusion: In spite of recent safety concerns for atypical antipsychotics, we found no increased risk of mortality in acutely ill pneumonia patients. Rather, we found a higher adjusted mortality rate for patients taking typical antipsychotics. The contrasting mortality risks for patients taking typical and atypical antipsychotics may represent unmeasured severity of illness or comorbidity. Regardless, any antipsychotics should be used with caution and the efficacy and safety of alternative agents should be considered.

Diabetes mellitus associated with clozapine therapy.

Clozapine is an atypical antipsychotic that is associated with certain adverse effects that limit its usefulness. Published case reports have associated clozapine with impairment of glucose tolerance, including the onset or exacerbation of diabetes mellitus. We report two patients who experienced diabetes mellitus associated with the agent.

Osteoporosis screening and treatment in women with schizophrenia: A controlled study

Study Objective. As patients with a major psychiatric disorder such as schizophrenia generally are less likely to have their medical illnesses diagnosed and medically managed, we investigated whether osteoporosis screening, prevention management, and/or drug therapy (i.e., clinical services for osteoporosis) are provided consistently to both women with schizophrenia and those without the disease.

Detoxification from benzodiazepines: Schedules and strategies

Management of benzodiazepine (BZD) tolerance is divided into low- and high-dose withdrawal. Low-dose withdrawal includes patients who have received manufacturer-recommended doses of BZD on a daily basis for longer than 1 month. Gradual tapering of the BZD over 4 weeks on an outpatient basis is suggested. High-dose withdrawal includes patients who have been ingesting doses of BZD greater than the equivalent of diazepam 40 mg/d for longer than 8 months. It is recommended that the patients be tolerance tested with diazepam and, if tolerant, tapered off medication as inpatients at a rate of 10% per day. Triazolobenzodiazepines may be exceptions to these recommendations. Alprazolam should be titrated at a rate of 0.5 mg three times a day regardless of whether the patient is being tapered for low- or high-dose withdrawal.

Patient and Facility Characteristics Associated With Benzodiazepine Prescribing for Veterans With PTSD

OBJECTIVE Practice guidelines used in the Veterans Health Administration (VHA) caution against benzodiazepine use by veterans with posttraumatic stress disorder (PTSD) because of inefficacy and safety concerns. Although use has declined, the VHA prescription rate is ≥30% nationally. To inform intervention design, this study examined patient- and facility-level correlates of benzodiazepine prescribing. METHODS This cross-sectional study used 2009 national administrative VHA data to identify veterans with PTSD, benzodiazepine prescriptions, and various patient and facility characteristics. Correlates of benzodiazepine prescribing were determined with multivariable hierarchical logit models. RESULTS Among 137 VHA facilities, 495,309 veterans with PTSD were identified, and 150,571 (30.4%) received a benzodiazepine prescription. Patient characteristics independently associated with benzodiazepine use included female gender, age ≥30 years, rural residence, service-connected disability ≥50%, Vietnam-era service, duration of PTSD diagnosis, and a comorbid anxiety disorder. However, case-mix adjustment for these variables accounted for <1% of prescribing variation. Facility characteristics independently associated with higher use included lower PTSD visit volume, higher rates of duplicate prescribing (concurrent use of more than one drug from a class), and lower rates of trazodone prescribing. These findings were corroborated in replication analyses. CONCLUSION The ultimate goal is to ensure consistent access to guideline-concordant PTSD treatment across the VHA. This study furthered this objective by identifying characteristics associated with benzodiazepine prescribing. Findings suggest that interventions could be designed to target individual high-volume prescribers or influence prescribing culture at the facility level.