Therapeutic Drug Monitoring Of Antipsychotics Research Articles

Guideline for the use of therapeutic drug monitoring of antipsychotics to individualize the selection of therapy in the treatment of exacerbation of schizophrenia

Significant individual variability in the concentration of antipsychotics (AP) and its impact on both the efficacy and safety of therapy has been shown in many studies. In this regard, the use of therapeutic drug monitoring (TDM) of AP seems to be a clinically relevant method for the individualization of psychopharmacotherapy in the treatment of exacerbations of schizophrenia. The purpose of this work was to develop recommendations on the use of TDM AP for the individualization of therapy for exacerbation of schizophrenia. Materials and methods. To develop recommendations, a literature search was performed on the Medline, Google Scolar and Elibrary databases and the materials of the dissertation of Potanin S.S. "The role of therapeutic drug monitoring of antipsychotics in the individualization of therapy for exacerbations of paroxysmal-progredient schizophrenia" were used. Results. The conducted literature search made it possible to classify AP according to the degree of expediency of TDM, to determine the optimal therapeutic concentrations for each drug, indications for TDM, and to develop a structured decision-making algorithm depending on the results obtained. The main indications for TDM AP in the treatment of exacerbation of schizophrenia are signs of impaired drug compliance, insufficient efficacy of therapy, pronounced dose-dependent side effects, and the addition of concomitant therapy that can significantly affect the concentration of AP. According to the results obtained, TDM is strongly recommended for clozapine, olanzapine and amisulpride, recommended for risperidone, paliperidone, aripiprazole, quetiapine, haloperidol, ziprasidone, perphenazine, sertindole, trifluoperazine, sulpiride and chlorpromazine, for other antipsychotics TDM may be useful in selected cases. A detailed decision-making algorithm is presented in the form of a table and is based on both the clinical situation and the results of TDM AP. Conclusion. Thus, TDM AP seems to be one of the most relevant and potentially close to the introduction into everyday practice methods of individualization of therapy for exacerbation of schizophrenia.

Blood Levels to Optimize Antipsychotic Treatment in Clinical Practice: A Joint Consensus Statement of the American Society of Clinical Psychopharmacology and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie.

The quantification of antipsychotic levels in blood, also known as therapeutic drug monitoring (TDM), is a potentially useful tool of modern personalized therapy that can be applied to augment antipsychotic use and dosing decisions. The application of TDM for antipsychotics can be helpful in numerous challenging clinical scenarios, such as lack of therapeutic response, relapse, or adverse drug reactions (ADRs) related to antipsychotic treatment. The benefits of TDM may be particularly evident in the treatment of highly vulnerable patient subgroups, such as children, adolescents, pregnant women, and the elderly. The main aim of this article is to aid clinicians who routinely prescribe antipsychotics to successfully apply TDM in routine clinical practice in order to help optimize the efficacy and safety of those antipsychotics. Participants were clinicians and researchers, members of the American Society of Clinical Psychopharmacology, and the Therapeutic Drug Monitoring Task Force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (Association of Neuropsychopharmacology and Pharmacopsychiatry). TDM literature on antipsychotics was critically reviewed to provide a condensed clinical decision-making algorithm with therapeutic reference ranges for blood antipsychotic levels, within which patients are most likely to respond and tolerate treatment, although TDM is not equally recommended/supported for all antipsychotics. A preliminary draft was prepared and circulated to the writing group members. Consensus was achieved in all cases, and resulting recommendations focused on following areas: steady-state and sampling time, levels of recommendations, indications, therapeutic reference ranges and laboratory alert levels, practical issues, and interpretation, as well as limitations. The utilization of TDM as a tool for problem solving in antipsychotic treatment offers a unique method to improve safety and efficacy. This consensus statement summarizes essential information on the routine use of TDM for antipsychotics and encourages clinicians to perform TDM with the appropriate indications as part of the clinical decision-making process.

Multiplexed therapeutic drug monitoring of antipsychotics in dried plasma spots by LC-MS/MS.

In this work, a convenient method for the therapeutic monitoring of seven common antipsychotic drugs in "dried plasma spot" samples has been developed. It is based on the liquid chromatography tandem mass spectrometry technique, operating in multiple reaction monitoring mode, and a straightforward procedure for the simultaneous extraction of all antipsychotics in a single step, with high extraction yield. The method was fully validated with proper accuracy, precision, selectivity and sensitivity, for all the drugs. Limits of quantification were 0.12, 1.09, 1.46, 1.47, 5.70, 1.32, 1.33 µg/L for haloperidol, aripiprazole, olanzapine, quetiapine, clozapine, risperidone, and paliperidone, respectively. Accuracy, intra- and interday precision values were<10% for all drugs at all concentration levels examined. The method was tested in the analysis of 30 plasma samples from real patients for each drug. The proposed analytical approach, by combining practical and logistical advantages of microsampling with liquid chromatography tandem mass spectrometry analytical performance, could offer an ideal strategy for accurate and timely therapeutic drug monitoring of antipsychotic drugs in most clinical settings, even in remote centers and/or in out-patient settings, bringing so many potential improvements in psychiatric patient care.

Dried Blood Spot Analysis for Therapeutic Drug Monitoring of Antipsychotics: Drawbacks of Its Clinical Application: Erratum.

Dried Blood Spot Analysis for Therapeutic Drug Monitoring of Antipsychotics: Drawbacks of Its Clinical Application: Erratum.

Parallel artificial liquid membrane extraction of psychoactive analytes: a novel approach in therapeutic drug monitoring.

Liquid-liquid extraction is widely used in therapeutic drug monitoring of antipsychotics, but difficulties in automation of the technique can result in long operational time. In this paper, parallel artificial liquid membrane extraction was used for extraction of serotonin-and serotonin-norepinephrine reuptake inhibitors from human plasma, and an approach to automate the technique was investigated. Eight model analytes were extracted from 125μl human plasma with recoveries in the range 72-111% (relative standard deviation [RSD] ≤12.8%). A semiautomated pipettor was successfully utilized in the procedure, reducing the manual handling time. Real patient samples were analyzed with satisfying accuracy. A semiautomated extraction of serotonin-and serotonin-norepinephrine reuptake inhibitors by parallel artificial liquid membrane extraction extraction was successfully performed.

Simple and Accurate Quantitative Analysis of 16 Antipsychotics and Antidepressants in Human Plasma by Ultrafast High-Performance Liquid Chromatography/Tandem Mass Spectrometry.

In psychopharmacology, treatment with psychotropic drugs is often suboptimal, mainly because of the high interindividual variability in pharmacokinetic properties. Therapeutic drug monitoring (TDM) can be a valuable tool for monitoring the individual effects of a prescribed dosage in a patient, and it facilitates antipsychotic treatment by increasing the effectiveness and safety of drugs and by reducing treatment costs. The aim of this study was to develop and validate an ultrafast liquid chromatography (UFLC) method with tandem mass spectrometric detection for the measurement of 16 antipsychotics and antidepressants in human plasma samples for TDM or other applications. The method was developed to replace traditional methods using the solid-phase extraction of proteins precipitated with methanol/acetonitrile containing 0.1% formic acid. Quantitative analysis was performed by UFLC combined with a tandem mass spectrometer using a Synergy 3u-Hydro-RP (2.0 × 50 mm, 3 μm) column with a mobile phase consisting of 0.1% formic acid and acetonitrile. A simple, fast, and sensitive UFLC-tandem mass spectrometry method for the simultaneous measurement of commonly used antipsychotics (aripiprazole, chlorpromazine, paliperidone, quetiapine, risperidone, ziprasidone, clozapine, and olanzapine), antidepressants (citalopram, escitalopram, mirtazapine, fluoxetine, paroxetine, sertraline, venlafaxine plus O-desmethylvenlafaxine, and fluvoxamine) and an antidementia drug (donepezil) has been developed. The total run time of the chromatographic separation was 6.0 minutes. The precision and accuracy varied from 0.90% to 14% and from 88.5% to 118%, respectively. A 6-point standard curve covering the clinically relevant ranges with a power function fit was applied for calibration. Ion suppression due to matrix effects and the internal standards were investigated. Their recoveries varied from 89% to 110%. This new validated method fulfills all criteria for TDM and was successfully applied in the routine TDM of antipsychotics and antidepressants at the First Affiliated Hospital of Kunming Medical University.

Are capillary DBS applicable for therapeutic drug monitoring of common antipsychotics? A proof of concept.

DBS sampling has been proposed as an alternative for venous blood collection in therapeutic drug monitoring (TDM) of antipsychotics. For implementation in routine practice, a comparison between capillary and venous blood concentrations is mandatory. A DBS method for quantification of antipsychotics was clinically validated. First, whole blood therapeutic ranges were calculated using the blood:serum ratio. Calculation of DBS:blood ratios and Passing-Bablok regression analysis demonstrated that concentrations obtained by DBS analysis were highly comparable to those obtained by conventional whole blood analysis. Clinical interpretation of serum, whole blood and DBS concentrations were highly identical (sensitivity 91.6-97.6%). This is the first clinical study demonstrating the value of DBS sampling in TDM of antipsychotics.

Antipsychotic therapeutic drug monitoring: psychiatrists' attitudes and factors predicting likely future use.

This study aimed to explore predictive factors for future use of therapeutic drug monitoring (TDM) and to further examine psychiatrists' current prescribing practices and perspectives regarding antipsychotic TDM using plasma concentrations. A cross-sectional study for consultant psychiatrists using a postal questionnaire was conducted in north-west England. Data were combined with those of a previous London-based study and principal axis factor analysis was conducted to identify predictors of future use of TDM. Most of the 181 participants (82.9%, 95% confidence interval 76.7-87.7%) agreed that 'if TDM for antipsychotics were readily available, I would use it'. Factor analysis identified five factors from the original 35 items regarding TDM. Four of the factors significantly predicted likely future use of antipsychotic TDM and together explained 40% of the variance in a multivariate linear regression model. Likely future use increased with positive attitudes and expectations, and decreased with potential barriers, negative attitudes and negative expectations. Scientific perspectives of TDM and psychiatrist characteristics were not significant predictors. Most senior psychiatrists indicated that they would use antipsychotic TDM if available. However, psychiatrists' attitudes and expectations and the potential barriers need to be addressed, in addition to the scientific evidence, before widespread use of antipsychotic TDM is likely in clinical practice.

The use of dried blood spots for quantification of 15 antipsychotics and 7 metabolites with ultra-high performance liquid chromatography - tandem mass spectrometry.

Therapeutic drug monitoring of antipsychotics is important in optimizing individual therapy. In psychiatric populations, classical venous blood sampling is experienced as frightening. Interest in alternative techniques, like dried blood spots (DBS), has consequently increased. A fast and easy to perform DBS method for quantification of 16 antipsychotics (amisulpride, aripiprazole, asenapine, bromperidol, clozapine, haloperidol, iloperidone, levosulpiride, lurasidone, olanzapine, paliperidone, pipamperone, quetiapine, risperidone, sertindole and zuclopenthixol) and 8 metabolites was developed. DBS were prepared using 25 μL of whole blood and extraction of complete spots was performed using methanol: methyl-t-butyl-ether (4:1). After evaporation, the extract was reconstituted in the mobile phase and 10 μL were injected on an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Separation using a C18 column and gradient elution with a flow rate of 0.5 mL/min resulted in a 6-min run-time. Ionization was performed in positive mode and a dynamic MRM method was applied. Median recovery was 66.4 % (range 28.7-84.5%). Accuracy was within the acceptance criteria, except for pipamperone (LLOQ and low concentration) and lurasidone (low concentration). Imprecision was only aberrant for lurasidone at low and medium concentration. All compounds were stable during 1 month at room temperature, 4 °C and -18 °C. Lurasidone was unstable when the extract was stored for 12 h on the autosampler. Absolute matrix effects (ME) (median 66.1%) were compensated by the use of deuterated IS (median 98.8%). The DBS method was successfully applied on 25-μL capillary DBS from patients and proved to be a reliable alternative for quantification of all antipsychotics except for olanzapine and N-desmethylolanzapine.

Bioanalytical methods for the determination of antipsychotic drugs

Antipsychotic drugs are popular for the treatment of schizophrenia and other psychoses. In general, antipsychotics are administered in oral doses of only a few milligrams per day and they are widely metabolized in the body. Therefore, the concentration of these drugs in plasma is very low (pg-ng/mL levels). In addition, therapeutic drug monitoring (TDM) of antipsychotic drugs has proven to be of notable value for determining poor compliance of patients and addressing the challenges associated with considerable genetic variability in their metabolism. Thus, in order to conduct pharmacology and toxicology studies and clinical TDM of antipsychotics, as well as address the challenges associated with polypharmacy and drug metabolism, highly sensitive, selective and accurate bioanalytical methods are essential. The most recent studies on the determination of antipsychotics will be reviewed, including separation techniques, sample pretreatment, detectors and validation.