Mauri MC, Volonteri LS, Colasanti A, Fiorentini A, De Gaspari IF, Bareggi SR. Clinical pharmacokinetics of atypical antipsychotics: a critical review of the relationship between plasma concentrations and clinical response. Clin Pharmacokinet 46: 359-388

Department of Internal Medicine, University of Milan, Milano, Lombardy, Italy
Clinical Pharmacokinetics (Impact Factor: 5.05). 02/2007; 46(5):359-88. DOI: 10.2165/00003088-200746050-00001
Source: PubMed


In the past, the information about the dose-clinical effectiveness of typical antipsychotics was not complete and this led to the risk of extrapyramidal adverse effects. This, together with the intention of improving patients’ quality of life and therapeutic compliance, resulted in the development of atypical or second-generation antipsychotics (SGAs). This review will concentrate on the pharmacokinetics and metabolism of Clozapine, risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole and sertindole, and will discuss the main aspects of their pharmacodynamics.
In psychopharmacology, therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding adverse effects by keeping long-term exposure to the minimal effective blood concentration. The rationale for using therapeutic drug monitoring in relation to SGAs is still a matter of debate, but there is growing evidence that it can improve efficacy, especially when patients do not respond to therapeutic doses or when they develop adverse effects.
Here, we review the literature concerning the relationships between plasma concentrations of SGAs and clinical responses by dividing the studies on the basis of the length of their observation periods.
Studies with clozapine evidenced a positive relationship between plasma concentrations and clinical response, with a threshold of 350–420 ng/mL associated with good clinical response. The usefulness of therapeutic drug monitoring is well established because high plasma concentrations of clozapine can increase the risk of epileptic seizures. Plasma clozapine concentrations seem to be influenced by many factors such as altered cytochrome P450 1A4 activity, age, sex and smoking.
The pharmacological effects of risperidone depend on the sum of the plasma concentrations of risperidone and its 9-hydroxyrisperidone metabolite, so monitoring the plasma concentrations of the parent compound alone can lead to erroneous interpretations. Despite a large variability in plasma drug concentrations, the lack of studies using fixed dosages, and discrepancies in the results, it seems that monitoring the plasma concentrations of the active moiety may be useful. However, no therapeutic plasma concentration range for risperidone has yet been clearly established. A plasma threshold concentration for parkinsonian side effects has been found to be 74 ng/mL. Moreover, therapeutic drug monitoring may be particularly useful in the switch between the oral and the long-acting injectable form.
The reviewed studies on olanzapine strongly indicate a relationship between clinical outcomes and plasma concentrations. Olanzapine therapeutic drug monitoring can be considered very useful in assessing therapeutic efficacy and controlling adverse events. A therapeutic range of 20–50 ng/mL has been found.
There is little evidence in favour of the existence of a relationship between plasma quetiapine concentrations and clinical responses, and an optimal therapeutic range has not been identified. Positron emission tomography studies of receptor blockade indicated a discrepancy between the time course of receptor occupancy and plasma quetiapine concentrations. The value of quetiapine plasma concentration monitoring in clinical practice is still controversial.
Preliminary data suggested that a therapeutic plasma amisulpride concentration of 367 ng/mL was associated with clinical improvement. A therapeutic range of 100–400 ng/mL is proposed from non-systematic clinical experience.
There is no direct evidence concerning optimal plasma concentration ranges of ziprasidone, aripiprazole or sertindole.

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    • "Although OLZ is effective for the acute management of psychosis, up to 80% of patients discontinue treatment within 5 years due to either a lack of long-term efficacy or drug-related adverse events (Schwenger et al., 2011). In this regard, plasma OLZ and metabolite (primarily N-desmethyl-OLZ) concentrations have been identified as important markers of both clinical response to OLZ and the occurrence of adverse effects such as weight gain, hyperinsulinemia, and hyperlipidemia (Perry et al., 2001; Mauri et al., 2007; Nozawa et al., 2008). Accordingly, therapeutic drug monitoring for OLZ is recommended in a number of clinical guidelines, and a therapeutic concentration range of 20–80 mg/l has been established (Baumann et al., 2004). "
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    ABSTRACT: Olanzapine (OLZ) is an atypical antipsychotic used in the treatment of schizophrenia and related psychoses. The metabolism of OLZ is complex and incompletely characterized. The aim of this study was to elucidate the enzymes and pathways involved in the metabolism of OLZ and to determine the kinetics of OLZ oxidation and glucuronidation by human liver microsomes (HLMs), and recombinant cytochrome P450 (rCYP) and recombinant UDP-glucuronosyltransferase (rUGT) enzymes. A UPLC-MS method was developed and validated to quantify OLZ, its four oxidative metabolites (N-desmethyl-OLZ, 2-hydroxymethyl-OLZ, 7-hydroxy-OLZ and OLZ-N-oxide), and two N-glucuronides (OLZ-10-N-glucuronide and OLZ-4'-N-glucuronide). Consistent with previous reports, UGT1A4, CYP1A2 and flavin-containing monooxygenase 3 play major roles in catalyzing the formation of OLZ-10-N-glucuronide, 7-hydroxy-OLZ and OLZ-N-oxide, respectively. In addition, a previously uncharacterized major contribution of CYP2C8 to OLZ-N-demethylation was demonstrated. The kinetics of OLZ metabolite formation (Km and Vmax) by HLMs, rCYP and rUGT enzymes were characterized in the presence of bovine serum albumin (BSA; 2% w/v). Consistent with the known effect of BSA on CYP1A2, CYP2C8 and UGT1A4 activities, Km values reported here are lower than previously reported values for OLZ metabolic pathways. In addition to CYP1A2-mediated OLZ-N-demethylation, these results suggest that other CYP enzymes, particularly CYP2C8, contribute significantly to oxidative OLZ metabolism through catalysis of OLZ-N-demethylation. The American Society for Pharmacology and Experimental Therapeutics.
    Full-text · Article · Sep 2015 · Drug metabolism and disposition: the biological fate of chemicals
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    • "The observed structural changes might represent a basis for known relatedness of amydala activity in schizophrenia to clinical state (Rasetti et al., 2009). Nevertheless, the value of quetiapine plasma concentration monitoring in clinical practice is still considered controversial (Mauri et al., 2007). While some authors doubt its usefulness in the context of clinical routine (Sparshatt et al., 2011), others argue in favour of measuring quetiapine levels to optimize individual pharmacotherapy (Wittmann et al., 2010). "
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    ABSTRACT: Schizophrenia is a severe, debilitating, chronic disease that is accompanied by morphologic changes within the brain. However, it is unclear to what extent alterations of grey and white matter in schizophrenia are linked to the disease itself, or whether they are a consequence of neuroleptic treatment. Typical and atypical antipsychotics exert differential effects on brain structure. Moreover, atypical antipsychotics may have distinct profiles with respect to grey matter in schizophrenic patients. Findings on drug-induced grey matter changes are heterogeneous due to variation in stage of illness, duration of treatment and use of multiple antipsychotics. Using voxel-based morphometry applied to high-resolution magnetic resonance images, we show that monotherapy with the atypical agent quetiapine (mean daily dose = 445 mg ± 200 s.d.) may induce structural brain changes in first-episode schizophrenia patients (N = 20) within 21 d of treatment. Specifically, we demonstrate longitudinal macroscopic changes (i.e. grey matter increases) in the left amygdalohippocampal region that were predicted by drug plasma levels but not daily doses. These structural alterations were accompanied by a clinical improvement of schizophrenic symptoms. Comparison with healthy controls (n = 30) showed that grey matter amount in the respective amygdalar region was significantly reduced in unmedicated first-episode schizophrenia patients. These findings suggest that drug-induced neuroplastic changes in schizophrenia can occur quickly and are dependent on pharmacokinetics.
    Full-text · Article · Jan 2014 · The International Journal of Neuropsychopharmacology
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    • "Second, we examined a single drug concentration (0.1 mM). It was an order of magnitude below the lowest effective concentration reported previously (Hagenfeldt et al., 1987) but still above usual therapeutic serum levels (haloperidol 0.05 μM, chlorpromazine 0.1 μM, clozapine 1.0 μM) (Van Putten et al., 1991; Ulrich et al., 1998; Mauri et al., 2007). On the other hand, in vivo tissue accumulation of antipsychotic drugs can exceed therapeutic serum concentrations by 10–30 fold (Kornhuber et al., 2006). "
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    ABSTRACT: Schizophrenia is associated with altered tyrosine transport across plasma membranes. This is typically demonstrated by measuring the uptake of radiolabeled tyrosine in cultured human fibroblasts. Our primary goal was to determine whether tyrosine uptake could be characterized using unlabeled tyrosine. A secondary goal was to assess the effect of antipsychotic drugs added during the incubation. Epithelium-derived fibroblast cultures were generated from patients with schizophrenia (n=6) and age-matched controls (n=6). Cells between cycles 8-12 were exposed to an amino acid free medium for 60min and then for 1min to media containing tyrosine (0.008-1.0mM). Amino acid levels were measured and Michaelis-Menten parameters determined. Uptake of tyrosine (0.5mM) was also measured in control cells after antipsychotic drugs were introduced during the depletion or uptake phases. Tyrosine uptake was sodium-independent. The maximal transport velocity (Vmax) was significantly lower in patients with schizophrenia than in controls (p<0.01). The transporter affinity (Km) did not differ between the groups. Tyrosine uptake was differentially affected (p<0.001) by inclusion of 10(-4)M haloperidol, chlorpromazine or clozapine during different periods of incubation. Dysregulated tyrosine kinetics in schizophrenia can be readily studied without the use of radiolabeled tracers. The data also indicate that tyrosine uptake may be subject to complex pharmacological effects.
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