Unbound Fraction of Clozapine Significantly Decreases with Elevated Plasma Concentrations of the Inflammatory Acute-Phase Protein Alpha-1-Acid Glycoprotein.

BACKGROUND: During inflammation, elevated total (unbound plus protein-bound) clozapine plasma concentrations have been observed. Elevated alpha-1-acid glycoprotein concentrations during inflammation are suggested to cause increased plasma clozapine-alpha-1-acid glycoprotein binding, resulting in elevated total clozapine plasma concentrations without significant changes in unbound concentrations. Here, we investigated the association between alpha-1-acid glycoprotein plasma concentrations and clozapine unbound fraction. METHODS: First, 25 and 60 µL of alpha-1-acid glycoprotein solution (20 mg/mL) were added to plasma samples (n = 3) of clozapine users (spiking experiment). Second, the association between alpha-1-acid glycoprotein plasma concentration and clozapine unbound fraction was assessed in patient samples (patient study). Samples were determined by liquid chromatography-tandem mass spectrometry. Data were analyzed with a paired t test (spiking experiment) and an unpaired t test (patient study). RESULTS: The spiking experiment showed significantly lower mean unbound fractions following 25- and 60-µL alpha-1-acid glycoprotein spikes (relative reductions of 28.3%, p = 0.032 and 43.4%, p = 0.048). In the patient study, total clozapine plasma concentrations were 10% higher in elevated (n = 6) compared with normal alpha-1-acid glycoprotein (n = 20) samples [525 µg/L vs. 479 µg/L, mean difference = 47 µg/L (95% confidence interval -217 to 310), p = 0.72]. Elevated alpha-1-acid glycoprotein samples had a 26% lower mean unbound fraction compared with normal samples [1.22% vs. 1.65%, mean difference = -0.43% (95% confidence interval -0.816 to -0.0443), p = 0.03]. CONCLUSIONS: Both the spiking experiment and patient study showed a significant association between elevated alpha-1-acid glycoprotein plasma concentrations and a lower clozapine unbound fraction. Future studies should include clinical data to examine whether this association is clinically relevant, suggesting any clozapine dose adjustments.

Analysis of potential drug-drug interactions in medical intensive care unit patients.

OBJECTIVE: To describe the frequency and type of potential drug-drug interactions (pDDIs) in a general intensive care unit (ICU) and to make recommendations to improve the management of these pDDIs. DESIGN: Retrospective observational study. SETTING: General ICU of a tertiary care hospital. SUBJECTS: All patients admitted for more than 24 hours between May 2009 and December 2010 who were prescribed at least one medication. MEASUREMENT AND MAIN RESULTS: Based on the G-Standaard, the Dutch national drug database, pDDIs were identified and classified into categories of potential clinical outcome and management advice. In total, 35,784 medication episodes were identified, resulting in 2887 pDDIs (8.1%). These 2887 pDDIs occurred in 1659 patients for a mean frequency of 1.7 (95% confidence interval [CI] 1.6-1.9) pDDIs per patient. Overall, 54% of the patients experienced at least one pDDI with pDDIs present during 27% of all ICU admission days. All pDDIs could be reconstructed using 81 of the 358 (23%) relevant unique pDDI pairs described in the G-Standaard. The most frequently occurring potential clinical consequence was an increased risk of side effects or toxicity (91% of the pDDIs) such as electrolyte disturbances and masking of hypoglycemia. The most important advised management strategy was monitoring (81%), consisting of monitoring of laboratory values (52%), clinical monitoring of toxicity or effectiveness (48%), or monitoring of physical parameters such as electrocardiogram and blood pressure (11%). CONCLUSION: Potential drug-drug interactions occur in 54% of all ICU patients, which is two times more than the rate seen in patients on general wards. A limited set of 20 pDDI pairs is responsible for more than 90% of all pDDIs. Therefore, it is worthwhile to develop guidelines for the management of these specific pDDIs. As the vast majority of the interactions can be managed by monitoring, advanced clinical decision support systems linking laboratory data to prescription data may be an effective risk management strategy.

Haloperidol dose when used as active comparator in randomized controlled trials with atypical antipsychotics in schizophrenia: comparison with officially recommended doses.

OBJECTIVE: To determine the doses of haloperidol as a comparator drug in randomized controlled trials (RCTs) with atypical antipsychotics in patients with schizophrenia and to compare these doses with the officially recommended doses for haloperidol in the United States and the United Kingdom. DATA SOURCES: We searched for RCTs conducted and published in English in full before January 2005 in which atypical antipsychotics were compared with haloperidol for the treatment of schizophrenia. We searched for Cochrane Reviews in which 1 of the following atypical antipsychotics was evaluated for the treatment of patients with schizophrenia, schizophreniform psychosis, or other primary psychosis: amisulpride, aripiprazole, olanzapine, quetiapine, risperidone, sertindole, and ziprasidone. For the gap between the end point of inclusion of the studies in the Cochrane Reviews and January 2005, we electronically searched the Cochrane Central Register of Controlled Trials for any further RCTs in which atypical antipsychotics were compared with haloperidol for the same indication. Search terms used were haloperidol and schizophren and haloperidol and psychotic, as well as the names of the selected atypical antipsychotics for the years that were not covered by the Cochrane Reviews. For each study, the required dose and mean dose of haloperidol were compared with officially recommended doses of haloperidol in U.S. (Food and Drug Administration) and U.K. (British National Formulary) guidelines. DATA SYNTHESIS: In all of the included studies (N = 49), the midpoints of the required doses were above the midpoint of the official recommended doses in the United States and United Kingdom for moderately ill patients. In 94% (U.S.) and 80% (U.K.) of the studies, they were above the upper border of the recommended doses. Compared with recommended doses for severely ill patients in both the United Kingdom and United States (range, 6-15 mg daily), in 17 studies (35%) the mean actual used dose was above the upper dose border for severely ill patients (15 mg daily). CONCLUSIONS: Nearly all randomized clinical trials used haloperidol in doses that were higher than the official recommended doses for moderately ill or even severely ill patients. Therefore, it is probable that the results of the RCTs were affected by the high dose of haloperidol, hampering the interpretation of the effects of atypical anti-psychotics in their comparison with haloperidol.

Risk of hip/femur fractures in patients using antipsychotics.

The objective of our study was to investigate whether use of antipsychotics is associated with hip/femur fractures and whether pharmacological differences between antipsychotics are related to the occurrence of fractures. A case-control study was conducted, in which cases were defined as patients with a hip/femur fracture. Each patient was matched to one control patient. The association between use of antipsychotics and the occurrence of hip/femur fractures was evaluated using conditional logistic regression. The study included 44,500 patients from 683 general practices from different geographical areas in the UK, registered within the General Practice Research Database (GPRD). Exposure to antipsychotics was categorized as "no use", "current use" and "prior use". Both current and prior use of antipsychotics were associated with an approximately two-fold increased risk of fractures. After adjustment for possible confounders, a small significant effect remained (Odds Ratios (OR) of 1.3). We did not find an association between dose of antipsychotics, or between the degree of blockade of the alpha-1 adrenoceptor or histamine-1 receptor and risk of fractures. The total number of days of antipsychotic use was significantly associated with an increased risk of hip/femur fractures. We conclude that there is a small increased risk of hip/femur fractures associated with the use of antipsychotics. This risk increases with long-term use.

Less medication switching after initial start with atypical antipsychotics.

We investigated the extent and time of switching to another oral antipsychotic in newly admitted in-patients that started oral antipsychotic therapy. In a retrospective follow-up study of 522 newly admitted patients who started with an oral antipsychotic, we applied a case-control analysis considering patients switching to another oral antipsychotics as cases. Association between patient characteristics and switching antipsychotic medication was evaluated using logistic regression analysis. A Kaplan-Meier plot was performed to analyse time to switch. Patients initially treated with an oral typical antipsychotic showed a twofold increased risk to switch to another antipsychotic compared to patients treated with an oral atypical antipsychotic (adjusted OR=1.79 95% CI=1.15-2.78). The Kaplan-Meier survival analysis revealed that patients started with a typical antipsychotic switched sooner compared to patients on atypical antipsychotics. Atypical antipsychotics are less frequently associated with switching in comparison with typical antipsychotics suggesting overall better treatment satisfaction.

Short-acting parenteral antipsychotics drive choice for classical versus atypical agents.

OBJECTIVE: The objective of this study was to investigate which antipsychotics (classical versus atypical) are prescribed in a psychiatric hospital and which determinants affect the choice for one of these two classes of antipsychotics in newly admitted patients. METHODS: In a retrospective cohort design, 522 newly admitted patients were followed from the date of admission until discharge from the hospital. In the cohort of newly admitted patients treated with an oral antipsychotic, a nested case-control study was conducted considering recipients of an atypical agent as cases. Controls were all other cohort members. The association of patient characteristics and the choice between classical versus atypical antipsychotics was studied using logistic regression analysis. The same analysis was performed with adjustment for possible confounding factors (age group, gender, DSM-IV diagnoses, use of short-acting parenteral antipsychotic, global assessment of functioning score, involuntary admissions and involuntary measures). RESULTS: Patients treated with classical oral antipsychotics were more often previously treated with short-acting parenteral antipsychotics than patients treated with atypical antipsychotics (40.8% vs 15.2%; adjusted OR=0.20 95% CI=0.09-0.44). No statistically significant difference was found between patients with different severities of disease. DISCUSSION: Availability of injectable forms seems to drive the choice for oral antipsychotic agents. Future introductions of short-acting parenteral atypical antipsychotics may have a large impact on first-choice oral antipsychotic treatment.