[Therapeutic drug monitoring of antipsychotic drugs in routine psychiatric practice]. / Terapevticheskii lekarstvennyi monitoring antipsikhoticheskikh preparatov v povsednevnoi psikhiatricheskoi praktike.

OBJECTIVE: To evaluate the relationship between daily doses of antipsychotic drugs, their serum concentrations, and characteristics of patients treated for schizophrenia or schizophreniform disorder in day-to-day clinical practice. MATERIAL AND METHODS: A total of 187 patients were included in the study, 77 (41.1%) patients were on monotherapy, and 110 (58.9%) patients received two or more antipsychotics. Patients age was 27.8±8.1 years, and their body weight was 79.8±15.6 kg. The sample was represented mainly by young men (93.0%). The proportion of smokers was 37.4%. The appropriate HPLC-MS/MS method was used for the simultaneous analysis of 8 antipsychotics and its active metabolites. Serum concentrations of the drugs aripiprazole (ARI), chlorpromazine (CPZ), haloperidol (HAL), zuclopenthixol (ZUC), clozapine (CLO), risperidone (RIS), quetiapine (QUE), olanzapine (OLA), norclozapine (N-desmethylclozapine, NOR), 9-hydroxyrisperidone (9-OH-RIS), dehydroaripiprazole (DGA) were measured. The serum concentration/dose ratio (C/D) was employed as the primary outcome measure, as doses were not kept constant during the study. The active antipsychotic fraction (drug+active metabolite, active moiety - AM) was also evaluated for RIS and ARI. In addition, the metabolite/parent ratio (MPR) was evaluated for RIS and ARI. RESULTS: A total of 265 biological samples were obtained, 421 and 203 measurements of the concentration of drugs and their metabolites were carried out, respectively. Overall, 48% of antipsychotics levels were in the expected therapeutic ranges, 30% were below therapeutic ranges, and 22% were above them. A total of 55 patients underwent dose adjustments or drug changes due to ineffectiveness or side-effects. It has been found that smoking reduces the level of C/D for CLO (p<0.01, Mann-Whitney test). We have established that comedication with CLO significantly increases the C/D ratio of QUE (p<0.05, Mann-Whitney test). We have not revealed any influence of weight and age of the subjects on the C/D. The dose-concentration regression relationships are formalized for all AP. CONCLUSION: Therapeutical drug monitoring (TDM) is an essential tool to personalize antipsychotic therapy. Careful analysis of TDM data can contribute significantly to the study of the impact of individual patient characteristics on systemic exposure to these drugs.

[Therapeutic drug monitoring of aripiprazole as part of the individualization of the pharmacotherapy of schizophrenia]. / Provedenie terapevticheskogo lekarstvennogo monitoringa aripiprazola v ramkakh individualizatsii farmakoterapii shizofrenii.

OBJECTIVE: To personalize pharmacotherapy with aripiprazole in patients with schizophrenia via therapeutic drug monitoring (TDM). MATERIAL AND METHODS: TDM of aripiprazole (ARI) and its active metabolite dehydroaripiprazole (DHA) was performed for patients diagnosed with schizophrenia (ICD-10 F20.00; F20.01; F20.02). Thirty-six parameters were assessed. To carry out TDM, the method of high-performance liquid chromatography with mass spectrometry was chosen employing a validated method. RESULTS: TLM was performed in a group of young patients: 26.5±10.1 years old, average weight 77.2±16.2 kg, average PANSS score 81.4±21.4, UKU score 14.5±3.9. An average ARI concentration was 18.4±7.9 mg, serum ARI concentration 417.9±362.4 ng/ml, serum DHA concentration 117.5±116.1 ng/ml and the total concentration 535.4±478.5 ng/ml. Equations of correlation dependences of concentration on dose are obtained for ARI and DHA. CONCLUSION: The results show the significant metabolism of ARI. A combined determination of the main substance and its active metabolite DHA in the patient's blood serum is advisable for correct assessment of the TLM result in patients with mental diseases.

[Therapeutic drug monitoring of risperidone and its active metabolite 9-hydroxyrisperidone in the treatment of schizophrenia]. / Terapevticheskii lekarstvennyi monitoring risperidona i ego metabolita 9-oksirisperidona pri terapii shizofrenii.

AIM: To conduct a routine therapeutic drug monitoring (TDM) and analyze its results for the optimization of pharmacotherapy. MATERIAL AND METHODS: Fifty-six inpatients (in total 68 samples) with various forms of schizophrenia were enrolled. High performance liquid chromatography with mass-spectrometric detection was used for quantitative determination of risperidone and 9-hydroxyrisperidone in the serum. RESULTS: Concentrations of risperidone and 9-hydroxyrisperidone were correlated with drug dose. Total concentrations in the blood at doses from 2 to 8 mg per day were distributed as follows: 44.1% were in the therapeutic, 29.4% in sub-therapeutic (<20 ng/mL) and 26.5% in conditionally toxic range (>60 ng/mL). CONCLUSIONS: Concentrations of risperidone and 9-hydroxyrisperidone did not follow the normal distribution. The results showed that monitoring of the total concentration of risperidone and its metabolite 9-hydroxyrisperidone was an effective tool for testing and quality control for the purpose of individualization of pharmacotherapy.

[Plasma levels of antipsychotics and the severity of side-effects in the treatment of schizophrenia exacerbation].

OBJECTIVE: To study a relationship between plasma levels of antipsychotics (AP) and severity of side-effects (SE) during the treatment of inpatients with exacerbation of schizophrenia. MATERIAL AND METHODS: The study included 39 patients treated with risperidone, haloperidol, zuclopenthixol, clozapine, aripiprazole or olanzapine as monotherapy or in combination of two AP. Blood sampling to measure the AP plasma level was performed twice (at 7-10 and 26-30 day from start of treatment), the levels of prolactin and glucose were determined once (at 26-30 day from start of treatment). Patients were assessed by psychometric scales PANSS and NSA and the side-effects scale UKU. RESULTS: The increased concentration of AP was noted in 33% of the patients. The high concentration of AP was significantly associated with akathisia and hyperkinesia (by UKU scale), NSA retardation factor and hyperprolactinemia. Patients with severe hyperprolactinemia were twice as likely to have a clinically significant depression. Increased blood glucose levels were observed in 18% of the patients, there was no significant association with AP plasma levels. Mental SE were most prominent, with a drift towards the neurological SE in the group with higher AP plasma levels. Chlorpromazine equivalent didn't significantly differ in the groups with normal, high and low AP concentrations. CONCLUSION: Elevated AP plasma levels, which were associated with some clinically significant SE and some negative symptoms, were found in most patients. In this regard, therapeutic drug monitoring is a promising method for the individualization of schizophrenia exacerbation treatment in routine clinical practice.

[Determination of homocysteine by tandem mass spectrometry with chemical ionization].

Homocysteine (Hcy) is an intermediate of methionine metabolism. High plasma Hcy concentrations are an independent risk factor for stroke, peripheral vascular disease, deep venous thrombosis, coronary disease, and cognitive deficiency. Apparently, it is a great importance to measure Hcy levels in human blood. A new method for the quantification of Hcy by means of reversed-phase LC/atmospheric pressure chemical ionization mass spectrometry has been developed. The MRM ion transition, m/z 136.0 ® 90.0 was used for Hcy quantification. The limit of detection was 0.4 mM, quantification was performed from 1 mM to 40 mM with coefficient of determination of R2=0,997. The method was applied successfully to Hcy determination in human blood.