Differences in serum concentration with valproate oral solution versus delayed-release divalproex in an adherent patient.

Background: Several different formulations of valproic acid derivatives are available in the United States. Although these formulations have different absorption characteristics, they are believed to be interchangeable, with the exception of the extended-release product. Case Report: A 31-year-old African American man with schizoaffective disorder was started on fluphenazine concentrate and valproate oral solution on admission to an inpatient unit. A 12-hour steady-state concentration, drawn on 1000 mg/day, resulted in 40.8 mg/L, and the dose continued to be titrated. Despite increasing doses, confirmed medication adherence, and accurate lab sampling, his concentrations remained low: 60.3 and 60.1 mg/L on 1500 mg/day, and 65.6 mg/L on 1750 mg/day. He was switched to divalproex delayed-release tablets, and his dose was increased to 2000 mg/day. Follow-up 12-hour steady-state concentrations were significantly higher, at 126.6 and 113.8 mg/L. It is theorized that the formulation of divalproex/valproic acid is what contributed to these differences in concentrations. Discussion: Valproic acid formulations are considered to be interchangeable, and several studies have demonstrated that chronic psychiatric inpatients stabilized on delayed-release divalproex may be safely switched to valproate oral solution without changes in psychiatric stability. This case demonstrates a significant difference in serum drug concentrations when switching from valproate oral solution to divalproex delayed-release tablets.

Impact on hospital-wide antipsychotic prescribing practices through physician peer comparison letters.

Peer comparison is a behavioral strategy that provides feedback to individuals on how they compare with others. It is used to improve health care quality, reduce inappropriate prescribing, and improve physician performance. There is very little data on peer comparison and the impact on system-wide prescribing practices, particularly with antipsychotics. To that end, the Maryland statewide pharmacy and therapeutics committee reviews hospital-level antipsychotic data for 5 facilities on a quarterly basis, including high doses and polypharmacy. One facility, Springfield Hospital Center, consistently stood out in 2016 as having higher rates of high doses of haloperidol, olanzapine, and quetiapine as well as patients receiving 3 or more antipsychotics. The pharmacist began to send out individual letters to the psychiatrists detailing their prescribing habits in these areas compared with other psychiatrists and the other state facilities. Over the course of 4 years, the percentage of patients on high doses of 3 antipsychotics substantially decreased. The percentage of patients on polypharmacy in the facility decreased, but not at the same rate as the other hospitals, leaving the facility even higher than the state average at the end of the 4-year period. Pharmacist-initiated physician peer comparison letters were associated with a considerable decrease in the prevalence of high-dose olanzapine, haloperidol, and quetiapine but did not appear to impact antipsychotic polypharmacy. This type of communication may be beneficial for stimulating system-wide changes in prescribing practices for high doses of antipsychotics; however, more individualized interventions are likely needed to reduce antipsychotic polypharmacy.

Toxic clozapine level as first indication of severe, acute infection.

BACKGROUND: Clozapine levels can be influenced by many factors, including pharmacogenomic variability, pharmacokinetic drug interactions, and infection/inflammation. The concentration-to-dose ratio (C/D), a measure of a medication's rate of metabolism and clearance, may increase during an acute infection due to decreased medication metabolism and clearance. CASE REPORT: A 56-year-old White man was restarted on clozapine and titrated up to 350 mg/d with therapeutic steady-state levels (C/D 1.11) on hospital day (HD) 69. At this time, he was also being treated for COPD exacerbation. For the next month, he continued to complain of cough, but vital signs and chest x-ray remained normal. Labs were unremarkable except for occasional leukocytosis that would resolve on repeat evaluation. A routine clozapine level drawn on HD 104, resulted on day 108 and showed clozapine toxicity with C/D 4.05, although the patient was asymptomatic. After receipt of labs on day 109, showing elevated WBC count, he was immediately sent to the emergency room where he was admitted for treatment of pneumonia. On return to the state hospital, the patient was continued on 100 mg clozapine and titrated to 200 mg/d based on low drug levels. He continued to do well on 200 mg/d clozapine with C/D averaging 1.13 (range, 0.75-1.52). DISCUSSION: Acute infection and illness can lead to significantly increased clozapine levels and toxicity, even if symptoms of toxicity are minimal or absent. This appears to be the first report of a toxic level being the first indication of severe medical illness.

Probable haloperidol decanoate-induced fever in an African American with benign ethnic neutropenia: A case report.

We present a case in which a patient developed fever and leukocytosis subsequent to each monthly haloperidol decanoate injection, an adverse reaction that does not meet the diagnostic criteria of neuroleptic malignant syndrome (NMS) or any previously reported adverse reaction for this medication. A patient being treated with haloperidol decanoate for psychosis experienced a fever within 3 days of injection and leukocytosis along with swelling, pain, and a "knot" feeling at the injection site. This recurred after each injection for several months. Muscle rigidity or changes in vital signs other than temperature were not noted. Temperature and injection site reactions resolved with administration of acetaminophen and ibuprofen. The elevation in temperature was discovered as a result of universal twice daily temperature monitoring implemented due to the COVID-19 pandemic. Reports of fever with antipsychotics are typically associated with NMS or heat stroke; the details of this case do not meet the clinical criteria for either. Similar reactions are reported for other antipsychotics, such as clozapine and olanzapine, but not for haloperidol. The recommendation was to discontinue use of the medication due to an unclear mechanism of the reaction.

Clozapine-associated renal failure: A case report and literature review.

One of clozapine's unrecognized potential side effects is renal insufficiency and nephritis. Although most clinicians are aware of the possibility of clozapine-induced myocarditis, less is known about other inflammatory disorders due to clozapine treatment. This patient was started on lithium and clozapine within 4 days of each other although lithium was discontinued after 7 days due to tremor. Routine labs showed an increase in serum creatinine, which was initially attributed to the recent lithium. However, the patient's kidney function continued to worsen, requiring discontinuation of clozapine despite a robust response to a low dose. Several years later, the patient's kidney function improved but has not returned to baseline. This literature review and case report illustrates the similarities in diagnostic presentation of clozapine-associated renal insufficiency as well as potential risk factors. More research should be conducted into the role concomitant sodium valproate and/or lithium play in the risk of clozapine-associated renal insufficiency.

Evaluation of the Safety of Clozapine Use in Patients With Benign Neutropenia.

OBJECTIVE: To determine if clozapine can be safely utilized in psychiatric patients with benign neutropenia. METHODS: A single-center, retrospective chart review study of records from 2001 to 2014 was conducted in an inpatient psychiatric hospital. Patients included had benign neutropenia prior to receiving clozapine and received clozapine using modified monitoring guidelines. All available laboratory values for absolute neutrophil count (ANC) before initiation and during treatment were evaluated. The primary endpoint was difference in ANC after initiation of clozapine from before clozapine. RESULTS: A total of 26 patients were reviewed. The mean age at clozapine initiation was 34 years. The majority were African-American (73% [n = 19]), with more men than women (73% [n = 19] vs 27% [n = 7]). The mean lowest ANC value was not significantly different after clozapine initiation compared to before (1.5× 10³ cells/mm³ and 1.4 × 10³ cells/mm³, respectively; P = .22). The overall mean ANC was significantly higher after initiation than before (2.63 × 10³ cells/mm³ and 2.13 × 10³ cells/mm³, respectively; P < .001). There were no cases of severe neutropenia (ANC < 0.5 × 10³ cells/mm³), and no patient was discontinued for falling below modified guideline limits. There were fewer occurrences of mild neutropenia (ANC < 2.0 × 10³ cells/mm³) after clozapine initiation than before (16.0% and 31.4%, respectively; P < .001). There were also fewer occurrences of moderate neutropenia (ANC < 1.5 × 10³ cells/mm³), with 2.1% after clozapine and 13.3% before (P < .001). CONCLUSIONS: Twenty-six patients with benign neutropenia were safely treated with clozapine. Pre-clozapine neutropenia did not predict increased risk for severe neutropenia with clozapine. Patients had significantly fewer episodes of mild and moderate neutropenia after receiving clozapine compared to before.