Reporting Patterns of Sialorrhea Comparing Users of Clozapine to Users of Other Antipsychotics: A Disproportionality Analysis Using VigiBase.

BACKGROUND: Sialorrhea is a non-life-threatening, but potentially invalidating adverse drug reaction (ADR) in patients using clozapine. In light of the very serious ADRs (agranulocytosis and myocarditis), sialorrhea is at risk to be overlooked by health care professionals. In this study, the sialorrhea reporting patterns of clozapine compared with other antipsychotics were assessed by evaluating differences in relative reporting frequency and reporter type. METHODS: A case/noncase disproportionality analysis using data from VigiBase (1968-2016) was performed. Reports of antipsychotics with "salivary hypersecretion" as ADR were considered as cases, and those with ADRs other than salivary hypersecretion were defined as noncases. Relative reporting frequencies were expressed as reporting odds ratios (RORs), and multivariate logistic regression was performed with the drug-ADR pair as unit of analysis to estimate RORs with 95% confidence intervals (CIs). RESULTS: A total of 1,169,254 drug-ADR pairs from 425,304 unique Individual Case Safety Reports were identified. Sialorrhea was relatively more frequently reported in clozapine (n = 2732 [1.1%]) compared with other antipsychotics (n = 2911 [0.31%]; ROR, 3.60; 95% CI, 3.41-3.79) and was reported relatively more often by consumers (ROR, 19.8; 95% CI, 15.1-25.9) compared with health care professionals (ROR, 2.44; 95% CI, 2.27-2.63). CONCLUSIONS: Sialorrhea was reported almost 4 times more often with clozapine use than with other antipsychotic use and was reported 8 times more often by patients than by health care professionals. This provides a signal of disproportion in sialorrhea occurrence among clozapine compared with other antipsychotics and in light of the disproportionality between reporter and an underreporting by health care professionals, underlining the importance to incorporate sialorrhea into the shared decision process when commencing clozapine therapy.

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.

Association between increased serum d-serine and cognitive gains induced by intensive cognitive training in schizophrenia.

Neuroscience-guided cognitive training induces significant improvement in cognition in schizophrenia subjects, but the biological mechanisms associated with these changes are unknown. In animals, intensive cognitive activity induces increased brain levels of the NMDA-receptor co-agonist d-serine, a molecular system that plays a role in learning-induced neuroplasticity and that may be hypoactive in schizophrenia. Here, we investigated whether training-induced gains in cognition were associated with increases in serum d-serine in outpatients with schizophrenia. Ninety patients with schizophrenia and 53 healthy controls were assessed on baseline serum d-serine, l-serine, and glycine. Schizophrenia subjects performed neurocognitive tests and were assigned to 50 h of either cognitive training of auditory processing systems (N = 47) or a computer games control condition (N = 43), followed by reassessment of cognition and serum amino acids. At study entry, the mean serum d-serine level was significantly lower in schizophrenia subjects vs. healthy subjects, while the glycine levels were significantly higher. There were no significant changes in these measures at a group level after the intervention. However, in the active training group, increased d-serine was significantly and positively correlated with improvements in global cognition and in Verbal Learning. No such associations were observed in the computer games control subjects, and no such associations were found for glycine. d-Serine may be involved in the neurophysiologic changes induced by cognitive training in schizophrenia. Pharmacologic strategies that target d-serine co-agonism of NMDA-receptor functioning may provide a mechanism for enhancing the behavioral effects of intensive cognitive training.

The Effect of Glycopyrrolate on Nocturnal Sialorrhea in Patients Using Clozapine: A Randomized, Crossover, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Nocturnal sialorrhea is one of the most frequent adverse events in clozapine treatment. Symptomatic management of sialorrhea usually consists of off-label treatment with anticholinergic agents. The aim of the current study is to evaluate the efficacy and safety of glycopyrrolate in patients using clozapine that experience sialorrhea. METHODS: In a double-blind randomized crossover trial, patients with nocturnal sialorrhea (n = 32) were randomized to treatment with glycopyrrolate 1 mg or placebo. This double-blinded phase was followed by an optional open label extension phase with glycopyrrolate 2 mg. Exposure periods consisted of 6 consecutive days and were separated with 1 washout week. The primary outcome was clinical improvement of nocturnal sialorrhea assessed by the Patient Global Impression of Improvement (PGI-I). RESULTS: The proportion of patients with a clinical improvement according to PGI-I did not significantly differ between 1 mg and placebo (18.8% vs 6.3%, P = 0.289); however, in patients using glycopyrrolate 2 mg once daily versus placebo, it did (43.5% vs 6.3%, P = 0.039). Glycopyrrolate was not associated with severe adverse events or worsening of cognitive adverse events. CONCLUSIONS: Glycopyrrolate 1 mg was not superior to placebo, whereas 2 mg showed a significant clinical improvement of nocturnal sialorrhea compared with placebo. Glycopyrrolate seemed to be a tolerable anticholinergic agent in the treatment of clozapine-associated sialorrhea.

Chronopharmacokinetics of once daily dosed aminoglycosides in hospitalized infectious patients.

BACKGROUND: hospitalized patients with serious infections treated with aminoglycosides are at risk of developing nephrotoxicity. Previous clinical studies have shown that the pharmacokinetics of aminoglycosides in humans follow a circadian rhythm. Therefore, the time of administration could have important clinical implications with respect to the risk of developing aminoglycoside-associated nephrotoxicity in patients treated with once daily dosing regimens. OBJECTIVE: To examine the effect of the time period of administration on aminoglycoside exposure and the incidence of nephrotoxicity in a large population of hospitalized patients with serious infections. SETTING: General ward and intensive care unit of a teaching hospital. METHOD: In this retrospective cohort study, patients treated with intravenous tobramycin or gentamicin were eligible for inclusion. Patients were divided into three groups by time of administration: morning, afternoon and night. MAIN OUTCOME MEASURE: Pharmacokinetic parameters and the incidences of nephrotoxicity were compared between the morning, afternoon and evening groups. Results 310 general ward and 411 intensive care unit patients were included. No significant differences were found in patient characteristics between the morning, afternoon and night groups. The time period of administration did not affect aminoglycoside pharmacokinetics or the incidence of nephrotoxicity. CONCLUSION: The time of administration has no effect on the pharmacokinetics or nephrotoxicity of once daily dosed aminoglycosides in hospitalized patients. Consequently, we advise aminoglycosides to be administered as soon as possible in case of (suspected) severe hospital-acquired infections and subsequent dosages to be based on therapeutic drug monitoring to optimize the efficacy/toxicity balance.

Fluorescence of neutrophil granulocytes as a biomarker for clozapine use.

Non-adherence to medication is a major issue in the treatment of schizophrenia in general and in particular for those treated with clozapine. A reliable tool to quantify patients long-term adherence to clozapine is currently unavailable. Enhanced FL3 neutrophil granulocyte fluorescence was serendipitously observed in a small population of schizophrenic patients treated with clozapine. The present study was aimed at assessing the association between clozapine use and FL3-fluorescence. A cross-sectional study was performed using data from the Utrecht Patient Oriented Database (UPOD). A total of 38,390 inpatients were included, of which 124 (0.33%) used clozapine. FL3-fluorescence was significantly higher (U=240,179, P<0.001) in clozapine users (mean (SD)=90.5 (11.8)) than in non-users (mean (SD)=69.8 (3.3)). Observed FL3-fluorescence was found to increase with increasing clozapine dose. The area under the receiver operating characteristic curve was 0.95. Our results confirm the association between use of clozapine and elevated FL3-fluorescence. Further research is needed to unravel the underlying mechanism and to investigate the true potential of FL3-fluorescence as a clozapine-adherence biomarker in clinical practice.

[Continuous and intermittent infusion of vancomycin equally effective: review of the literature]. / Continue en intermitterende infusie van vancomycine even effectief.

OBJECTIVE: To compare the efficacy of continuous vancomycin infusion with intermittent vancomycin infusion based on clinical endpoints. DESIGN: Systematic review of the literature. METHOD: Sixty articles on comparative studies on continuous and intermittent vancomycin infusion were found in Pubmed. Of these, the English-language articles on studies in adults were selected. Only articles in which a comparison was made in terms of clinical endpoints were included. RESULTS: Six studies were included in which the differences between continuous and intermittent infusions were assessed in terms of the clinical endpoints. In the 2 prospective studies, no statistically significant differences in efficacy between the two methods of administration were found. A prospective study and retrospective study suggested that continuous infusion of high-dose vancomycin in patients with osteomyelitis may be more effective than intermittent infusion. There were no clear differences in side effects, although nephrotoxicity seemed to occur less rapidly and less often with continuous vancomycin infusion. CONCLUSION: The available literature showed that continuous infusion of vancomycin is as effective as intermittent administration. In addition, continuous administration is cheaper and monitoring of serum levels is simpler. This offers the possibility of discharging specific patients more quickly from hospital and facilitates home care with vancomycin.