The Imperfective Past

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

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 antipsychotics in their comparison with haloperidol.</p

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 antipsychotics in their comparison with haloperidol

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

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