Assessment of cognitive function in long-term Hodgkin lymphoma survivors, results based on data from a major treatment center in Hungary.

INTRODUCTION: Nowadays, more than 80% of newly diagnosed classical Hodgkin lymphoma (HL) patients can be cured and become long-term survivors due to risk and response-adapted treatment strategies. A well-known side effect is cognitive dysfunction that appears in HL patients after chemotherapy. In the present study, we aimed to measure cognitive dysfunction in our HL patients in this study and to find potential correlations between patient-related factors, the signs and symptoms of their diseases, or therapeutic factors. METHODS: We carried out a computer-assisted assessment (CANTAB) of cognitive dysfunction in 118 patients. We examined the domains of visual memory, attention, working memory, and planning. RESULTS: The median age of 64 females and 54 males at diagnosis was 29 (13-74) and 41 (21-81) years at the completion of CANTAB. Fifty-two percent of all patients showed cognitive impairment. Attention was impaired in 35% of patients, the working memory and planning were impaired in 25%, while visual memory was affected in 22%. All the three functions showed a significant association with inactive employments status. A close correlation was found between visual memory/working memory and planning, higher age at HL diagnosis or the completion of CANTAB test, and disability pensioner status. DISCUSSION: Our investigation suggests that patients with inactive employment status and older age require enhanced attention. Their cognitive function and quality of life can be improved if they return to work or, if it is not possible, they receive a cognitive training.

Employment status and health related quality of life among Hodgkin-lymphoma survivors'- results based on data from a major treatment center in Hungary.

BACKGROUND: Due to risk and response adapted treatment strategies, more than 80% of newly diagnosed classical Hodgkin lymphoma (HL) patients can be cured, and become long-term survivors. However, a high proportion of survivors suffer from treatment-related long-term side effects such as secondary malignancy, organ failure, persistent fatigue and psychological distress. The aim of this study was to evaluate psychological distress and its risk factors among our HL survivors. METHODS: One hundred sixty-three (50% female) adult HL survivors were contacted between January 1, 2012 and march 31, 2015 in our outpatient centre. The patients were asked to complete a standardized, validated, self-administered Hungarian questionnaire with demographic questions and the following scales: Hospital anxiety and depression scale (HADS14), general health questionnaire (GHQ12), sense of coherence (SOC13) perceived stress scale (PSS4), dysfunctional attitude scale (DAS17). Disease and treatment data were acquired from hospital records. RESULTS: Majority of HL survivors are in early adulthood, our most important goal should be to return them to normal life after their lymphoma is cured. The employment status at the time of survey seemed to be crucial so patients were divided into either active (n = 93) or inactive (n = 47) group. Retired survivors (n = 19) were excluded from the subgroup analysis. Psychological distress was significantly lower in active patients. Multiple logistic regression analysis showed significant differences between the inactive and active subgroups, such as age at diagnosis (≥30 years or below, p = 0.001), education level (below college vs. college, p = 0.032) and treatment related long-term side effects (yes vs. no, p < 0.001). Predictors for treatment-related long-term side effects are female gender (p = 0.011), chemotherapy protocol (ABVD vs. other, p < 0.001). CONCLUSIONS: Our data suggest that employment status and treatment-related long-term side effects play a critical role in the health related quality of life outcome among Hungarian HL survivors.

UNANSWERED QUESTIONS IN THE TRANSCRANIAL MAGNETIC STIMULATION TREATMENT OF PATIENTS WITH DEPRESSION.

According to the WHO fact sheet depression is a common mental disorder affecting 350 million people of all ages worldwide. Transcranial Magnetic Stimulation (TMS) is a technique which allows the investigator to stimulate and study cortical functions in healthy subjects and patients suffering from various mental and neurological disorders. In the early 1990s, studies revealed that it is possible to evoke long term mood changes in healthy volunteers by rapid rate repetitive, TMS (rTMS) over the frontal cortex. Subsequent studies involving depressed patients found frontal cortical rTMS administered daily to be clinically effective. In the past two decades, numerous trials examined the therapeutic potential of rTMS application in the treatment of mood disorders with constantly evolving treatment protocols. The aim of this paper is to review the literature of the past two decades, focusing on trials addressing the efficacy and safety of rTMS in depressed patients. Our primary goal is to evaluate the results in order to direct future studies which may help investigators in the development of treatment protocols suitable in hospital settings. The time is not far when TMS devices will be used routinely by practitioners primarily for therapeutic purpose rather than clinical research. To our knowledge, a widely accepted "gold standard" that would offer the highest efficacy, with the best tolerability has not been established yet. In order to approach this goal, the most important factors to be addressed by further studies are: localization, frequency, intensity, concurrent medication, maintenance treatments, number of pulses, trains, unilateral, or bilateral mode of application.

[Ketamine administration in case of severe, therapy resistant depressed patient, case report]. / Ketamin alkalmazása súlyos, terápiarezisztens depressziós beteg esetében.

Objective - In our case report we present the treatment of a female patient suffering from therapy resistant depression. This procedure is not in practice in Hungary at present, the aim of our work to reproduce the findigs of international studies in domestic circumstances. Matter - Major depression is a common, chronic and severe mental disorder, with 16.2% lifetime prevalence. Many international randomized, placebo controlled trials found administration of ketamine infusion effective in depressed patients. Methods - Since ketamine is an anesthetic agent, its administration was performed in the post-operative monitoring room of our hospital operating-room, supervised by an anesthesiologist. According to formerly published data, a dose of 0.5 mg/kg of body weight was administered intravenously in 40 minutes by perfusor. The drug was administered in a same manner fifteen days later. Subject - The patient was admitted to our inpatient ward with severe depression. During two months of combined antidepressant therapy her condition has not improved significantly. Approval for off label drug indication was granted with urgency by the National Institute of Quality and Organizational Development in Healthcare and Medicines. Results - During the two treatments the Hamilton Depression Rating Scale 21 items rating scale score was reduced to 8 from the baseline 28, the Hamilton Anxiety Rating Scale score was reduced to 6 from 25, Beck Depression Inventory was reduced to 9 from 20. Upon administration of the drug no severe adverse event was detected, the mild dissociative state related to ketamine was ceased in a short period of time. Discussion - With administration of 0.5 mg/kg ketamine the authors managed to achieve rapid improvement in a therapy resistant depressed patient, without permanent side effects. Our future plan is to repeat the use of the drug within a double-blind, placebo controlled trial in order to prove its efficacy in hospital settings.

Automated Neuropsychological Test Battery in depression -- preliminary data.

AIMS: Studies have demonstrated neuropsychological deficits across a variety of cognitive domains in patients with major depressive disorder (MDD) during acute episode. However, limited data are available concerning whether these abnormalities persist in the remission phase. METHODS: In the present study CANTAB (Cambridge Automated Neuropsychological Test Battery) was used to evaluate the cognitive impairment associated with depression during acute episode and in remission. 25 patients with MDD during an acute episode and 11 patients also during remission were tested with CANTAB. RESULTS: During the acute episode, Delayed matching to sample, Paired associate learning, Spatial recognition memory, Rapid visual processing and Visuospatial planning were impaired. In remission the improvement of visual learning ability, spatial recognition memory, psychomotor speed, and executive function was observed. CONCLUSIONS: The results suggest that MDD is associated with neurocognitive dysfunctions in different domains, the most prominent deficit was found in the Paired associate learning test, which requires both the elaboration of "frontal strategies" and the "mnemonic processes". Cognitive impairment was found to improve partly in remission, suggesting that an individual's current mood interacts with the ability to perform a cognitive task. Besides these state markers, trait deficits are important because cognitive impairments which do not improve in remission might serve as endophenotypes of depression.

[P300 in mild cognitive impairment and in dementia]. / P300 enyhe kognitív zavarban és demenciában.

OBJECTIVES: The late component of the event-related potential (ERP), P300 is a marker for cognitive brain functions. The objective of this study was to examine P300 parameters in dementia and in mild cognitive impairment (MCI), to examine whether there is a correlation between the changes in P300 parameters and the type and severity of dementia, and to determine P300 abnormalities in MCI in relation to the presence/absence of CT/MRI abnormalities. METHOD: Auditory event-related potentials, P300 were recorded in 28 MCI patients (14 of them with normal CT/MRI findings and 10 subjects with mild ventricular enlargement). In another group of patients, 31 demented patients were examined, of whom 17 patients were diagnosed with Alzheimer's dementia (AD), and 14 patients with vascular dementia (VD). Forty healthy volunteers served as the control group. RESULTS: Mean P300 latency was significantly increased for both demented patient-groups. We found that prolongation of P300 latency was correlated with the severity of dementia. Mean P300 amplitude was significantly decreased in both groups of demented patients. In MCI, the mean latency of P300 was significantly longer among patients with mild cerebral atrophy compared to control volunteers and no significant changes were found for MCI patients with normal CT/MRI findings. Mean P300 amplitude was decreased only in demented patients. CONCLUSIONS: The prolongation of P300 latency was significant among patients with both vascular and Alzheimer's dementia, and also among MCI patients with mild cerebral atrophy. The severity of dementia is positively correlated with P300 latency; however, this prolongation is independent of the type of dementia. The structural brain changes in MCI are related to P300 latency prolongation and thus may indicate an increased risk for developing dementia in MCI patients.

Does the severity of depressive symptoms after stroke affect long-term survival? An 18-year follow-up.

OBJECTIVE: We tested whether the severity of depressive symptoms in acute stroke and 4 years later are predictors of long-time survival. METHOD: We evaluated the severity of stroke in 82 patients with acute stroke by the Barthel index, the Scandinavian Stroke Scale and the Orgogozo scale, and we also quantified the severity of depressive symptoms by the Beck and the Hamilton scales in the first week of stroke, in 1995. We re-evaluated the scales 4 years after stroke in 41 out of 48 survivors. We checked the survival status of the initial cohort 18 years after stroke. In the assessment Kaplan-Meier graphs were constructed and the outcomes between groups were compared with log-rank tests. RESULTS: Clinically important depressive symptoms (≥10 on the Beck scale) was present in 16 patients (19,5%) with acute stroke one week after admission. Case fatality was 41% at 4 years and 84% at 18 years after stroke. Those patients who survived at 4 years were significantly younger (p<0,05). Depressive symptoms in acute stage were not independent predictor of the length of survival. More severe strokes were associated with more severe depressive symptoms 4 years after stroke. In the survival subgroup of patients, those who had more severe depression (≥10 on the Beck scale) at 4 years, had shorter post-stroke survival than those with milder or no depression (Mann-Whitney test, p = 0.022; log-rank-test, p = 0.047). In multivariate analyses, adjusted for age, sex, stroke severity and the severity of depressive symptoms, age, sex and stroke severity remained the significant predictors of the length of survival. CONCLUSIONS: The severity of depressive symptoms either in the acute phase or 4 years after stroke is not an independent predictor of the length of survival in an 18-year follow-up.

Automated Neuropsychological Test Battery (CANTAB) in mild cognitive impairment and in Alzheimer's disease.

Neuropsychological deficits, such as poor episodic memory, are consistent features of mild cognitive impairment and also that of early stage of dementia. The aim of the present study was to detect cognitive dysfunction among patients with Alzheimer's disease or with mild cognitive impairment (MCI), which refers to a transitional state between the cognition of normal aeging and mild dementia regarded as a high-risk condition for the development of clinically probable Alzheimer's disease (AD). Computerized tests of memory, attention and executive functions were studied in groups of AD subjects (n=15) and MCI subjects (n=25). On all measures, the performance of the AD group was significantly weaker compared to healthy individuals or to the MCI group. The performance of both the AD and MCI patients in the Paired Associate Learning test was significantly impaired, which may suggest that MCI patients are already in the early stages of the disease.

Antipsychotic drugs and QTc prolongation: the potential role of CYP2D6 genetic polymorphism.

Although the most common, and usually serious, side effects of first-generation (or typical) antipsychotic drugs, such as Parkinsonism, dystonias and tardive dyskinesia, were known from early times, their cardiovascular safety was not properly in the focus of treatment management. The growing evidence of these drug-related cardiac changes and the appearance of potentially fatal dysrhythmias have increased the interest on their safety profile. Thus, the introduction of the new second-generation (atypical) antipsychotic drugs put emphasis on the preregistration evaluation of the potential cardiac side effects and electrocardiogram predictors (QT interval lengthening). In spite of this, these drugs do not appear to be exempt from these potential risks. The present review summarizes up-to-date knowledge about the cardiac safety of antipsychotic drugs, and analyses the role of drug metabolic processes (CYP2D6 genetic polymorphism) in the complex pathophysiology of the phenomenon. In addition, some recommendations are formulated.

Clinical Decision Making and Mental Health Service Use Among Persons With Severe Mental Illness Across Europe.

OBJECTIVE: The study explored relationships between preferences for and experiences of clinical decision making (CDM) with service use among persons with severe mental illness. METHODS: Data from a prospective observational study in six European countries were examined. Associations of baseline staff-rated (N=213) and patient-rated (N=588) preferred and experienced decision making with service use were examined at baseline by using binomial regressions and at 12-month follow-up by using multilevel models. RESULTS: A preference by patients and staff for active patient involvement in decision making, rather than shared or passive decision making, was associated with longer hospital admissions and higher costs at baseline and with increases in admissions over 12 months (p=.043). Low patient-rated satisfaction with an experienced clinical decision was also related to increased costs over the study period (p=.005). CONCLUSIONS: A preference for shared decision making may reduce health care costs by reducing inpatient admissions. Patient satisfaction with decisions was a predictor of costs, and clinicians should maximize patient satisfaction with CDM.

Brain blood flow changes measured by positron emission tomography during an auditory cognitive task in healthy volunteers and in schizophrenic patients.

OBJECTIVE: Cognitive deficit is an essential feature of schizophrenia. One of the generally used simple cognitive tasks to characterize specific cognitive dysfunctions is the auditory "oddball" paradigm. During this task, two different tones are presented with different repetition frequencies and the subject is asked to pay attention and to respond to the less frequent tone. The aim of the present study was to apply positron emission tomography (PET) to measure the regional brain blood flow changes induced by an auditory oddball task in healthy volunteers and in stable schizophrenic patients in order to detect activation differences between the two groups. METHOD: Eight healthy volunteers and 11 schizophrenic patients were studied. The subjects carried out a specific auditory oddball task, while cerebral activation measured via the regional distribution of [15O]-butanol activity changes in the PET camera was recorded. RESULTS AND DISCUSSION: Task-related activation differed significantly across the patients and controls. The healthy volunteers displayed significant activation in the anterior cingulate area (Brodman Area - BA32), while in the schizophrenic patients the area was wider, including the mediofrontal regions (BA32 and BA10). The distance between the locations of maximal activation of the two populations were 33 mm and the cluster size was about twice as large in the patient group. CONCLUSIONS: The present results demonstrate that the perfusion changes induced in the schizophrenic patients by this cognitive task extends over a larger part of the mediofrontal cortex than in the healthy volunteers. The different pattern of activation observed during the auditory oddball task in the schizophrenic patients suggests that a larger cortical area - and consequently a larger variety of neuronal networks--is involved in the cognitive processes in these patients. The dispersion of stimulus processing during a cognitive task requiring sustained attention and stimulus discrimination may play an important role in the pathomechanism of the disorder.

Cognitive functions in prepsychotic patients.

OBJECTIVE: Cognitive dysfunctions are now widely understood as an essential feature of schizophrenia. A great number of cognitive disturbances have been described in drug-naive first-episode patients as well. The full-blown psychotic symptoms are usually preceded by a longer prodromal period, in which non-specific psychological disturbances are already present. The late prodromal phase is also coined as the prepsychotic state, with attenuated, isolated psychotic symptoms. The aim of the present study was to detect cognitive dysfunctions among young adults at the prepsychotic stage with the use of a standardized computer based cognitive test battery. METHOD: Eleven (9 men, 2 women) young Hungarian adults referred to the Outpatient Clinic of the Department of Psychiatry at the University of Debrecen were studied. The patients were re-evaluated for psychotic symptoms after 12 months. The patients had no history of psychiatric disorders or psychotic episodes and were referred by general practitioners on account of non-specific emotional or behavioural abnormalities. The subjects were asked to perform a series of 13 computerized neuropsychological tests of the Cambridge Neuropsychological Test. The performance of the patients were compared to that of the standardized database of the Cambridge Neuropsychological Test. RESULTS AND DISCUSSION: The performance of the prepsychotic patients was significantly lower compared to the healthy individuals in the paired associate learning (PAL, p<0.001), Spatial recognition memory (SRM, p<0.05), Rapid visual processing (RVP, p<0.05), and Spatial working memory (SWM, p<0.05) tests. CONCLUSION: Cognitive deficits were found mainly in attentional, frontal and prefrontal cognitive functions. These impairments may be present at the early stages of the development of psychosis and the standardized cognitive test battery (CANTAB) might be a useful tool for the detection of early cognitive impairments and provide a rationale for early intervention in individuals at risk of developing psychosis.

Reduced completed suicide rate in Hungary from 1990 to 2001: relation to suicide methods.

BACKGROUND AND METHOD: Changes in the rate of completed suicides and in the suicide methods used in Hungary between 1990 and 2001 were evaluated using the database of the Hungarian Central Statistical Office. RESULTS: During this period of time, the suicidal mortality rate decreased by 27.9%. A major part (62%) of this decrease was due to the less frequent use of poisonous substances and drug overdose, particularly of psychotropics. CONCLUSION: Beside the more widespread treatment of depression and other mental disorders, the improved safety of pharmacotherapy and the removal of the most toxic pesticides and chemicals from everyday use might have contributed to the reduction of the suicide rate in Hungary.

[Cognitive functions in prepsychotic and negative-symptom schizophrenic patients]. / Kognitív funkciók prepszichotikus és negatív tünetes szkizofrén betegekben.

BACKGROUND: Relationship between schizophrenia and cognitive functions has been reported by several studies. Our work group examined the changes of cognitive functions in prepsychotic patients without any relevant psychiatric disorder in their anamnesis, and also in schizophrenic patients with predominantly negative symptoms. METHODS: Measures were carried out by Cambridge Neuropsychological Test Automated Battery (CANTAB), a complex computer-based test battery of 13 tests covering a wide range of cognitive functions. 11 prepsychotic (9 male, 2 female) and 14 negative-symptom schizophrenic patients (all male) took part in the study. RESULTS: Prepsychotic patients showed significant (p < 0.05) impairment in the tests of visual memory, spatial recognition memory, spatial working memory and sustained attention. In patients with negative-symptoms significant deficits were also found (p < 0.05) in the delayed matching to sample, the working memory test, and in the intra-extradimensional shift--an analogue of Wisconsin Card Sorting Test. CONCLUSION: The present results show CANTAB may be a useful tool to detect the emergence of psychosis in an early phase, and also it has been found that in schizophrenic patients with predominantly negative symptoms further areas of cognition are also affected. The results may provide a better understanding about the background of the disorder, and the early recognition of the cognitive deficits may help to initiate a specific therapy in proper time. This could result in the slowing of the progression and an improved chance of recovery.

QTc interval lengthening is related to CYP2D6 hydroxylation capacity and plasma concentration of thioridazine in patients.

Thioridazine cardiotoxicity has been associated with a prolonged heart-rate corrected QT (QTc) interval. However, no systematic studies have been performed on patients at therapeutic doses. The present study aimed to evaluate the influence of dose and plasma concentration of thioridazine and CYP2D6 enzyme status on the QTc interval in psychiatric patients. Sixty-five Spanish European psychiatric patients receiving thioridazine antipsychotic monotherapy were studied. The plasma levels of thioridazine and its metabolites were determined by high-performance liquid chromatography. All patients were phenotyped for CYP2D6 activity with debrisoquine during treatment. Thirty-five patients (54%) had a QTc interval over 420 ms. The lengthening of QTc interval was correlated with plasma concentration (p < 0.05) and daily dose (p < 0.05) of thioridazine. CYP2D6 enzyme hydroxylation capacity, evaluated by debrisoquine metabolic ratio (MR) (p < 0.05) and thioridazine/mesoridazine ratio (p < 0.05), was also correlated with QTc intervals. The present study shows the relationship between QTc interval lengthening among psychiatric patients treated at therapeutical doses with the dose and the plasma concentration of thioridazine. Since debrisoquine MR has been shown to be correlated with the QTc intervals, CYP2D6 enzyme hydroxylation capacity might be relevant in determining the risk for QTc interval lengthening. Patients with impaired CYP2D6 enzyme activity due to enzyme inhibition by thioridazine might be more prone to increased risk of sudden death due to torsade de pointes type cardiac dysrhythmia.

QTc interval, CYP2D6 and CYP2C9 genotypes and risperidone plasma concentrations.

The role of certain drug metabolizing enzymes in cardiotoxicity, such as CYP2D6 for thioridazine, has been suggested. Risperidone has been shown to inhibit the delayed rectifier leading to lengthening of cardiac repolarization. The heart-rate corrected QT (QTc) interval lengthening has been reported in psychiatric patients receiving risperidone under steady-state conditions. CYP2D6 is involved in the metabolism of risperidone to 9-hydroxy (OH)-risperidone. CYP2C9 enzyme is also involved in the metabolism of several psychotropic drugs, although there are no data about its implication in risperidone metabolism. The present study aimed to evaluate the influence of CYP2D6 and CYP2C9 genotypes, and plasma concentrations of risperidone and 9-OH-risperidone on the QTc interval in patients under steady-state conditions. The relevance of CYP2D6 and CYP2C9 genotypes on risperidone metabolism was also analysed. Thirty-five White European psychiatric patients receiving risperidone monotherapy were studied. QTc interval was longer (p < 0.05) in subjects with one active CYP2D6 gene compared to those with two. The number of CYP2D6 active genes was related to the dose-corrected plasma concentration of risperidone (p < 0.05), the active moiety (risperidone plus 9-OH-risperidone) (p < 0.05) and the risperidone/9-OH-risperidone ratio (p < 0.05). CYP2C9 genotypes were not related to plasma concentrations of risperidone or 9-OH-risperidone, nor QTc interval. The results suggest that CYP2D6, but not CYP2C9, may be related to QTc lengthening during treatment with risperidone. The effect of the CYP2D6 genotype in risperidone metabolism is also shown.

Analysis of diclofenac and its metabolites by high-performance liquid chromatography: relevance of CYP2C9 genotypes in diclofenac urinary metabolic ratios.

In humans, diclofenac is metabolised to 4'-hydroxy (OH), 3'-OH and 5-OH metabolites. The polymorphic CYP2C9 is involved in the metabolism of diclofenac to 4'-OH diclofenac and 3'-OH diclofenac. The aim of the present study was to develop a high-performance liquid chromatographic method to simultaneously measure diclofenac and its metabolites in urine, suitable for metabolic studies. After liquid-liquid extraction the compounds were separated in a reversed-phase column and measured by ultraviolet absorption at 282 nm. For all compounds intra-day and inter-day variations were less than 7%, and the limits of quantitation were 0.25 mg/l. No analytical interference with endogenous compounds was found. The relationship between diclofenac metabolic ratios among different CYP2C9 genotypes is reported. The CYP2C9*3/*3 subject had the highest diclofenac/4'-OH ratios. However no difference was found between CYP2C9*2/*2 and *1/*1 genotypes. The chromatographic method developed was sensitive and reliable for the measurement of diclofenac and its metabolites simultaneously in human urine, and is suitable for use in diclofenac metabolism studies.

Determination of fluoxetine and norfluoxetine in human plasma by high-performance liquid chromatography with ultraviolet detection in psychiatric patients.

A rapid high-performance liquid chromatographic method is described for the simultaneous determination of the widely used antidepressant drug, fluoxetine and its principal metabolite norfluoxetine in plasma. After liquid-liquid extraction the compounds were separated in a reversed-phase column and assayed by ultraviolet absorption at 226 nm. The analytical interference from psychoactive drugs and their metabolites was also studied. The extraction recoveries were 93 and 87% for norfluoxetine and fluoxetine, respectively. The limit of quantitation under the described conditions was 14 nmol/l for both compounds. The method was found to be reproducible with coefficients of variation less than 10%. A great variability in plasma concentrations of fluoxetine and norfluoxetine as well as in fluoxetine/norfluoxetine ratios was found among the 29 patients studied. This result suggests the implication of genetically polymorphic enzymes, presumably CYP2D6, CYP2C9 and CYP2C19 in the metabolism of fluoxetine to norfluoxetine. Therapeutic drug monitoring should thus be useful in patients treated with regular doses.

Determination of risperidone and 9-hydroxyrisperidone in human plasma by liquid chromatography: application to the evaluation of CYP2D6 drug interactions.

A high-pressure liquid chromatography with ultra-violet detection method for the simultaneous determination of risperidone and 9-hydroxyrisperidone in plasma after liquid-liquid extraction has been developed. The limit of quantitation was 5 nmol/L, and the inter-day coefficient of variation was less than 8% for both compounds. The mean recoveries of risperidone and 9-hydroxyrisperidone added to plasma were 96.8 and 99.4%, with an intra-day coefficient of variation of under 5 and 6%, respectively. Studies of analytical interference showed that the most commonly co-administered antidepressants and benzodiazepines did not interfere. The method was used for the determination of the plasma concentrations of a schizophrenic patient treated daily with an oral dose of 4.5 mg risperidone. The patient suffered severe extrapyramidal side-effects after adding risperidone to his previous medication of haloperidol and levomepromazine. The risperidone plasma concentration was well above the average (182 nmol/L), which suggests that a pharmacokinetic interaction occurred, presumably due to inhibition of the enzyme CYP2D6.

Reproducibility over time of the urinary diclofenac/4'-OH diclofenac ratio among different CYP2C9 genotypes.

Diclofenac has been used for the evaluation of CYP2C9 activity in vitro as well as in vivo with varying results. The present study was aimed at evaluating the reproducibility of the urinary diclofenac/4'-OH diclofenac ratio among different CYP2C9 genotypes in healthy volunteers. The study of CYP2C9 genotypes in the family of a CYP2C9*3/*3 subject is also reported. The urinary diclofenac/4'-OH diclofenac ratio was determined on two occasions within a period of 9-12 months, and was found to be correlated (r = 0.83, p < 0.05). The mean (+/- SD) of diclofenac/4'-OH diclofenac ratio was 1.5 times higher among subjects carrying CYP2C9*3 allele (CYP2C9*1/*3 and CYP2C9*2/*3 genotypes) (0.91 +/- 0.28), compared to CYP2C9*1/*1 subjects (0.60 +/- 0.11). The results show that the urinary diclofenac/4'-OH diclofenac ratio might be used to study CYP2C9 in humans. The data agree with previous studies showing that the CYP2C9*3 allelic variant seems to cause a decreased CYP2C9 hydroxylation capacity.