Coprescription of levodopa with antipsychotics in a population of 84,596 psychiatric inpatients from 1994 to 2008.

INTRODUCTION: Patients on levodopa therapy frequently require additional antipsychotic pharmacotherapy. However, consideration must be given to antagonistic interactions on dopamine receptors between levodopa and antipsychotics, and efficacy and safety of such combinations. We therefore aimed to explore the practice and rationale of coprescription between levodopa and antipsychotics in psychiatric patients. METHODS: A descriptive retrospective study based on cross-sectional prescription data repeatedly collected from psychiatric inpatients through the international Drug Safety in Psychiatry (AMSP) program between 1994 and 2008 was undertaken. RESULTS: Within a population of 84 596 psychiatric patients the prevalence of levodopa therapy was 1.0% (n=886). Among those patients on levodopa therapy 59.6% (n=528) also received antipsychotics. Quetiapine coprescription increased after its first marketing in 2000 to 45.9% in 2008. Coprescription of clozapine and olanzapine decreased from up to 25 and 22%, respectively, before to less than 10% after the introduction of quetiapine. Coprescribing of other antipsychotics remained approximately stable with average prevalences between 6 and less than 1%. DISCUSSION: Quetiapine has now replaced clozapine as the most frequently coprescribed neuroleptic in psychiatric patients with levodopa therapy. This is in accordance with recent data indicating a low potential for clinically relevant interactions with levodopa and efficacy against psychosis in levodopa-treated patients. The combined use of antipsychotics other than quetiapine and clozapine with levodopa is less common and generally not supported by appropriate evidence.

AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint eff ort.

AGNP Consensus Guidelines for Therapeutic Drug Monitoring in Psychiatry: Update 2011.

Therapeutic drug monitoring (TDM), i. e., the quantification of serum or plasma concentrations of medications for dose optimization, has proven a valuable tool for the patient-matched psychopharmacotherapy. Uncertain drug adherence, suboptimal tolerability, non-response at therapeutic doses, or pharmacokinetic drug-drug interactions are typical situations when measurement of medication concentrations is helpful. Patient populations that may predominantly benefit from TDM in psychiatry are children, pregnant women, elderly patients, individuals with intelligence disabilities, forensic patients, patients with known or suspected genetically determined pharmacokinetic abnormalities or individuals with pharmacokinetically relevant comorbidities. However, the potential benefits of TDM for optimization of pharmacotherapy can only be obtained if the method is adequately integrated into the clinical treatment process. To promote an appropriate use of TDM, the TDM expert group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued guidelines for TDM in psychiatry in 2004. Since then, knowledge has advanced significantly, and new psychopharmacologic agents have been introduced that are also candidates for TDM. Therefore the TDM consensus guidelines were updated and extended to 128 neuropsychiatric drugs. 4 levels of recommendation for using TDM were defined ranging from "strongly recommended" to "potentially useful". Evidence-based "therapeutic reference ranges" and "dose related reference ranges" were elaborated after an extensive literature search and a structured internal review process. A "laboratory alert level" was introduced, i. e., a plasma level at or above which the laboratory should immediately inform the treating physician. Supportive information such as cytochrome P450 substrate- and inhibitor properties of medications, normal ranges of ratios of concentrations of drug metabolite to parent drug and recommendations for the interpretative services are given. Recommendations when to combine TDM with pharmacogenetic tests are also provided. Following the guidelines will help to improve the outcomes of psychopharmacotherapy of many patients especially in case of pharmacokinetic problems. Thereby, one should never forget that TDM is an interdisciplinary task that sometimes requires the respectful discussion of apparently discrepant data so that, ultimately, the patient can profit from such a joint effort.

Adverse drug reactions following nonresponse in a depressed patient with CYP2D6 deficiency and low CYP 3A4/5 activity.

A 47-year-old male taxi driver experienced multiple adverse drug reactions during therapy with clomipramine (CMI) and quetiapine for major depressive disorder, after having been unsuccessfully treated with adequate doses of mirtazapine and venlafaxine. Drug serum concentrations of CMI and quetiapine were significantly increased and pharmacogenetic testing showed a poor metabolizer status for CYP2D6, low CYP3A4/5 activity and normal CYP2C19 genotype. After reduction of the CMI dose and discontinuation of quetiapine, all ADR subsided except for the increase in liver enzymes. The latter improved but did not normalize completely, even months later, possibly due to concomitant cholelithiasis.

[Therapeutic drug monitoring: A pharmacotherapeutic tool in psychiatry]. / Arzneimittelspiegel als pharmakotherapeutisches Werkzeug bei der Behandlung mit Psychopharmaka.

Therapeutic drug monitoring (TDM) is used increasingly for managing psychiatric outpatients, where the preanalytic error risk is high. Blood samples must be collected under steady-state conditions immediately before ingestion of the morning dose or before the next injection. In order to interpret the plasma levels accurately, age, gender, ethnicity, compliance, drug dosage, renal and hepatic function and comedication incl. smoking habits and diet (esp. caffeine intake and consumption of grapefruit juice) have to be taken into account. If in doubt, aberrant plasma levels should be confirmed by a second control under optimized conditions. Pharmacogenetic testing enables the identification of abnormal metabolizers. TDM and pharmacogenetic tests are useful tools to improve pharmacotherapy by preventing dose-dependent adverse drug events, optimizing dosage during long-term treatment and identifying ultrarapid metabolizers and malcompliance.

[Why do schizophrenic patients smoke?]. / Warum rauchen Schizophreniepatienten?

Patients suffering from schizophrenia are known to show an increased prevalence of nicotine addiction. The aim of this paper is to elucidate the relationship between schizophrenia and (chronic) use of nicotine. Nicotine seems to improve cognitive functions critically affected in schizophrenia, in particular sustained attention, focused attention, working memory, short-term memory, and recognition memory. Furthermore, several studies using evoked potentials (P50 paradigm) and prepulse inhibition of the acoustic startle reflex suggest that deficient preattentive information processing, a core feature of schizophrenia illness, is improved following treatment with nicotine. Smoking can also improve extrapyramidal secondary effects of antipsychotic medication and it induces cytochrome P4501A2, an enzyme system involved in the metabolism of several antipsychotics. There is substantial evidence that nicotine could be used by patients with schizophrenia as a "self-medication" to improve deficits in attention, cognition, and information processing and to reduce side effects of antipsychotic medication. Possible pharmacotherapeutic approaches for the regulation of abnormal neurotransmission at nicotinic acetylcholine receptors are discussed.

Therapeutic monitoring of antidepressants in the era of pharmacogenetics studies.

As for other drugs, there is a large interindividual variability of the plasma concentrations of antidepressants for a given dose. Within the last 2 decades, a very large number of pharmacogenetic studies have made it possible to understand the importance of genetic factors on the disposition of drugs in the organism, many of them at the levels of drug metabolism. Polymorphism of CYP2D6 and of other drug-metabolizing enzymes may thus lead to very large differences in drug exposure between patients and possibly also to toxicity or ineffective drug concentrations in some subjects. In consequence, dose recommendations of antidepressants based on genotypes, justified by the principle of administering bioequivalent individualized drug doses, are now proposed. However, blood (and thus possibly brain) concentrations also depend on other factors than the genetic makeup of the patients. Therapeutic drug monitoring of antidepressants allows us to take into account the influence of factors such as comedications, diet, smoking habit, impaired organ function, and compliance. Therapeutic drug monitoring and genotyping are thus complementary, and their combined use contributes to improve pharmacotherapy with antidepressants and other drugs.

Nonresponse to clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene.

Clozapine (CLO), an atypical antipsychotic, depends mainly on cytochrome P450 1A2 (CYP1A2) for its metabolic clearance. Four patients treated with CLO, who were smokers, were nonresponders and had low plasma levels while receiving usual doses. Their plasma levels to dose ratios of CLO (median; range, 0.34; 0.22 to 0.40 ng x day/mL x mg) were significantly lower than ratios calculated from another study with 29 patients (0.75; 0.22 to 2.83 ng x day/mL x mg; P < 0.01). These patients were confirmed as being CYP1A2 ultrarapid metabolizers by the caffeine phenotyping test (median systemic caffeine plasma clearance; range, 3.85; 3.33 to 4.17 mL/min/kg) when compared with previous studies (0.3 to 3.33 mL/min/kg). The sequencing of the entire CYP1A2 gene from genomic DNA of these patients suggests that the -164C > A mutation (CYP1A2*1F) in intron 1, which confers a high inducibility of CYP1A2 in smokers, is the most likely explanation for their ultrarapid CYP1A2 activity. A marked (2 patients) or a moderate (2 patients) improvement of the clinical state of the patients occurred after the increase of CLO blood levels above the therapeutic threshold by the increase of CLO doses to very high values (ie, up to 1400 mg/d) or by the introduction of fluvoxamine, a potent CYP1A2 inhibitor, at low dosage (50 to 100 mg/d). Due to the high frequency of smokers among patients with schizophrenia and to the high frequency of the -164C > A polymorphism, CYP1A2 genotyping could have important clinical implications for the treatment of patients with CLO.