Productive and physiological responses of lactating dairy cows supplemented with phytogenic feed ingredients.

This experiment compared milk production, milk composition, and physiological responses in lactating dairy cows supplemented with or without a mixture of condensed tannins, encapsulated cinnamaldehyde, curcumin, capsaicin, and piperine. Thirty-six lactating, multiparous, pregnant ¾ Holstein × » Gir cows were maintained in a single drylot pen with ad libitum access to water and a total-mixed ration and were milked twice daily (d -7 to 84). On d 0, cows were ranked by days in milk (86 ± 3 d), milk yield (27.8 ± 1.0 kg), body weight (BW; 584 ± 10 kg), and body condition score (BCS; 3.04 ± 0.06) and assigned to receive (SUPP; n = 18) or not (CON; n = 18) 30 g/cow daily (as-fed basis) of Actifor Pro (Delacon Biotechnik GmbH; Steyregg, Austria). From d 0 to 84, SUPP cows individually received (as-fed basis) 15 g of Actifor Pro mixed with 85 g of finely ground corn through self-locking headgates before each milking of the day. Each CON cow concurrently received 85 g (as-fed basis) of finely ground corn through self-locking headgates. Throughout the experimental period (d -7 to 84), cows from both treatments were administered 500 mg of sometribove zinc at 14-d intervals and were monitored daily for morbidity, including clinical mastitis. Individual milk production was recorded daily, whereas milk samples were collected weekly for analysis of milk composition. Cow BW, BCS, and blood samples were also collected weekly. Cows receiving SUPP gained more BCS (P = 0.05) and had greater (P = 0.04) milk yield during the experiment compared with CON cows (0.22 vs. 0.07 of BCS, SEM = 0.05; 29.5 vs. 27.9 kg/d, SEM = 0.5). Milk composition did not differ (P ≥ 0.15) between SUPP and CON cows; hence, SUPP cows also had greater (P ≤ 0.02) production of fat-corrected and energy-corrected milk. Incidence of clinical mastitis did not differ (P ≥ 0.49) between SUPP and CON cows. No treatment differences were also detected (P ≥ 0.21) for serum concentrations of glucose and serum urea N. Mean serum haptoglobin concentration during the experiment was greater (P = 0.05) in CON vs. SUPP cows. Cows receiving SUPP had less (P ≤ 0.04) serum cortisol concentrations on d 21 and 42, and greater (P ≤ 0.05) serum concentrations of insulin-like growth factor-I on d 7, 35, and 63 compared with CON cows (treatment × day interactions; P ≤ 0.02). Collectively, supplementing phytogenic feed ingredients improved nutritional status and milk production of lactating ¾ Holstein × » Gir cows.

Developmental delay in communication among toddlers and its relationship to caregiving behavior among violence-exposed, posttraumatically stressed mothers.

OBJECTIVES: This study aimed to understand if maternal interpersonal violence-related posttraumatic stress disorder (IPV-PTSD) is associated with delayed language development among very young children ("toddlers"). METHODS: Data were collected from 61 mothers and toddlers (ages 12-42 months, mean age = 25.6 months SD = 8.70). Child expressive and receptive language development was assessed by the Ages and Stages Questionnaire (ASQ) communication subscale (ASQCS) that measures language acquisition. Observed maternal caregiving behavior was coded from videos of 10-min free-play interactions via the CARE-Index. Correlations, Mann-Whitney tests, and multiple linear regression were performed. RESULTS: There was no significant association between maternal IPV-PTSD severity and the ASQCS. Maternal IPV-PTSD severity was associated with continuous maternal behavior variables (i.e. sensitive and controlling behavior on the CARE-Index) across the entire sample and regardless of child gender. Maternal sensitivity was positively and significantly associated with the ASQCS. Controlling behavior was negatively and significantly associated with the ASQCS. CONCLUSIONS: Results are consistent with the literature that while maternal IPV-PTSD severity is not associated with child language delays, the quality of maternal interactive behavior is associated both with child language development and with maternal IPV-PTSD severity. Further study is needed to understand if the level of child language development contributes to intergenerational risk or resilience for relational violence and/or victimization.

[Psychiatric care for asylum seekers in Geneva: a multidisciplinary approach for individualized care]. / Soins psychiatriques pour les requérants d'asile à geneve. Une approche multidisciplinaire pour préserver la singularité des soins.

Asylum seekers constitute a vulnerable population insofar as they are submitted to numerous stress factors which facilitate the emergence of mental disorders, such as low socio-economic status, forced separation from loved ones and exposure to violence. Asylum seekers who consult at our community psychiatry facility usually have short-term residence permits, live in collective housing and do not speak the local language. The most frequent diagnoses are depressive disorder (64.7%) and post-traumatic stress disorder (34.5%). Due to their specific clinical and social situation and to the involvement of several professionals in these situations, a specialized psychiatric intervention coordinated with the rest of the network seems necessary.

Screening for bipolar disorder among outpatients with substance use disorders.

BACKGROUND: Comorbidity of bipolar disorder and alcohol or substance abuse/dependence is frequent and has marked negative consequences on the course of the illness and treatment compliance. The objective of this study was to compare the validity of two short instruments aimed at screening bipolar disorders among patients treated for substance use disorders. METHODS: The Mood Disorder Questionnaire (MDQ) and the Hypomania Checklist-32 (HCL-32) were tested with reference to the mood section of the Structured Clinical Interview for DSM-IV axis I disorders (SCID) in 152 patients, recruited in two outpatient clinics providing specialized treatment for alcohol and opiate dependence. RESULTS: According to the SCID, 33 patients (21.7%) had a diagnosis within the bipolar spectrum (two bipolar I, 21 bipolar II and 10 bipolar not otherwise specified). The HCL-32 was more sensitive (90.9% vs. 66.7%) and the MDQ more specific (38.7% vs. 77.3%) for the whole sample. The MDQ displayed higher sensitivity and specificity in patients treated for alcohol than for opiate dependence, whereas the HCL-32 was highly sensitive but poorly specific in both samples. Both instruments had a positive predictive value under 50%. CONCLUSIONS: Caution is needed when using the MDQ and HCL-32 in patients treated for substance use disorders.

Liver kidney microsomal type 1 antibodies reduce the CYP2D6 activity in patients with chronic hepatitis C virus infection.

Liver kidney microsomal type 1 (LKM-1) antibodies have been shown to decrease the CYP2D6 activity in vitro and are present in a minority of patients with chronic hepatitis C infection. We investigated whether LKM-1 antibodies might reduce the CYP2D6 activity in vivo. All patients enrolled in the Swiss Hepatitis C Cohort Study and tested for LKM-1 antibodies were assessed (n = 1723): 10 eligible patients were matched with patients without LKM-1 antibodies. Patients were genotyped for CYP2D6 variants to exclude individuals with a poor metabolizer genotype. CYP2D6 activity was measured by a specific substrate using the dextromethorphan/dextrorphan metabolic ratio to classify patients into four activity phenotypes. All patients had a CYP2D6 extensive metabolizer genotype. The observed phenotype was concordant with the CYP2D6 genotype in most LKM-negative patients, whereas only three LKM-1 positive patients had a concordant phenotype (six presented an intermediate and one a poor metabolizer phenotype). The median DEM/DOR ratio was sixfold higher in LKM-1 positive than in LKM-1 negative patients (0.096 vs. 0.016, P = 0.004), indicating that CYP2D6 metabolic function was significantly reduced in the presence of LKM-1 antibodies. In chronic hepatitis C patients with LKM-1 antibodies, the CYP2D6 metabolic activity was on average reduced by 80%. The impact of LKM-1 antibodies on CYP2D6-mediated drug metabolism pathways warrants further translational studies.

Mindfulness-based cognitive therapy for bipolar disorder: a feasibility trial.

BACKGROUND: The present open study investigates the feasibility of Mindfulness-based cognitive therapy (MBCT) in groups solely composed of bipolar patients of various subtypes. MBCT has been mostly evaluated with remitted unipolar depressed patients and little is known about this treatment in bipolar disorder. METHODS: Bipolar outpatients (type I, II and NOS) were included and evaluated for depressive and hypomanic symptoms, as well as mindfulness skills before and after MBCT. Patients' expectations before the program, perceived benefit after completion and frequency of mindfulness practice were also recorded. RESULTS: Of 23 included patients, 15 attended at least four MBCT sessions. Most participants reported having durably, moderately to very much benefited from the program, although mindfulness practice decreased over time. Whereas no significant increase of mindfulness skills was detected during the trial, change of mindfulness skills was significantly associated with change of depressive symptoms between pre- and post-MBCT assessments. CONCLUSIONS: MBCT is feasible and well perceived among bipolar patients. Larger and randomized controlled studies are required to further evaluate its efficacy, in particular regarding depressive and (hypo)manic relapse prevention. The mediating role of mindfulness on clinical outcome needs further examination and efforts should be provided to enhance the persistence of meditation practice with time.

Self- and clinician-rated Montgomery-Asberg Depression Rating Scale: evaluation in clinical practice.

BACKGROUND: Time- and cost-effective self-rating scales of depressive symptoms are particularly valuable for frequent use in large-scale effectiveness trials. The aim of the present study was to examine the psychometric properties of the French version of the self-rated Montgomery-Asberg Depression Rating Scale (MADRS-S) and determine whether it might complement the MADRS in monitoring depression severity and change over time in routine clinical practice. METHODS: Sixty-three adult outpatients with a current depressive episode completed the MADRS-S and were interviewed with the MADRS on two occasions, within a 1-month interval. RESULTS: All patients readily accepted the MADRS-S. It showed good to excellent internal consistency (Cronbach's alpha 0.85 at Time 1; 0.94 at Time 2). Its factor structure revealed that a single component explained a large proportion of variability (47.0% at Time 1; 68.8% at Time 2). Concurrent validity of the self- and clinician-rated versions was good (Pearson's correlation coefficients for total scores 0.81 at Time 1; 0.91 at Time 2). The MADRS-S was sensitive to change over the 4-week observation period (correlation of 0.71 between change scores on self- and clinician-rated instruments). LIMITATIONS: Generalizability is restricted to outpatients with moderate to severe depression, and the MADRS-S ability to measure treatment effects needs to be examined. CONCLUSIONS: The present study indicates that the MADRS-S displays favourable psychometric properties and suggests that it might be a valid complement to the MADRS, both in research settings and clinical practice.

Self-rated residual symptoms do not predict 1-year recurrence of depression.

BACKGROUND: Residual depressive symptoms are generally documented as a risk factor for recurrence. In the absence of a specific instrument for the assessment of residual symptoms, a new 25-item Depression Residual Symptom Scale (DRSS) was elaborated and tested for recurrence prediction over a 1-year follow-up. SAMPLING AND METHODS: Fifty-nine patients in remission after a major depressive episode (MDE) were recruited in two centres. They were assessed with the DRSS and the Montgomery-Asberg Depression Rating Scale (MADRS) at inclusion and followed for 1 year according to a seminaturalistic design. The DRSS included specific depressive symptoms and subjective symptoms of vulnerability, lack of return to usual self and premorbid level of functioning. RESULTS: Severity of residual symptoms was not significantly associated with increased risk of recurrence. However, DRSS score was significantly higher among patients with three or more episodes than one to two episodes. Number of previous episodes and treatment interruption were not identified as significant predictors of recurrence. CONCLUSION: The proposed instrument is not predictive of depressive recurrence, but is sensitive to increased perception of vulnerability associated with consecutive episodes. Limitations include small sample size, seminaturalistic design (no standardisation of treatment) and content of the instrument.

[Current topics in pharmacokinetics and pharmacogenetics of antidepressant drugs]. / Actualités pharmacocinétiques et pharmacogénétiques des antidépresseurs.

For antidepressants as well as for other drugs, personalized prescription has become a major challenge, provided the large interindividual variability encountered both at the pharmacokinetic and the efficacy and tolerance levels. Better identification of the numerous relevant factors and quantification of their effects are prerequisites to progress in that direction. On the basis of recent literature, genetic factors are first reviewed, including polymorphisms of genes coding for drug-metabolizing enzymes, transporters and pharmacodynamic target molecules. Current recommendations with respect to therapeutic drug monitoring of antidepressants and use of pharmacogenetic testing are then summarized.

Frequency of dysphoria and mixed states.

BACKGROUND: Mixed states are a complex entity in the field of mood disorders. Dysphoria has been advocated as an important clinical dimension of mixed states. The objective of this work is to study the frequency of dysphoria within a population of patients with DSM-IV major depressive and/or manic episodes and to determine if it may help establish diagnostic criteria for subthreshold cases of depressive or manic mixed states. SAMPLING AND METHODS: A total of 165 patients were assessed using the Mini International Neuropsychiatric Interview complemented by a section defining dysphoria as a constellation of 3 among 4 symptoms (inner tension, irritability, aggressive behavior and hostility). RESULTS: When classifying patients according to the number of symptoms of the opposite polarity, changes in the frequency of dysphoria revealed a clear contrast between the 2 opposite manic and depressive poles and the full mixed state (DSM-IV definition). The frequency of dysphoria was 17.5% in pure depression, 22.7% in pure mania and 73.3% in full mixed state. Two threshold effects were identified: (1) the frequency of dysphoria increased from 17.5 to 61.1% (p = 0.002) when the number of manic symptoms in DSM-IV depressed patients increased from 0 to 1, and (2) dysphoria increased from 14.3 to 69.2% (p = 0.057) when the number of depressive symptoms increased from 2 to 3 in DSM-IV manic patients. CONCLUSION: Dysphoria is strongly but not necessarily associated with mixed states. When used as a clinical marker for mixed states, dysphoria confirms the modern delimitations of sub-threshold mixed states by specifying the required number of symptoms of the opposite polarity (which could be lower for depressive mixed states than for manic mixed states). The study has limitations related to the inclusion of patients who are not drug-free, to the definition of dysphoria and to the sample size.

Phenomenology of mixed states: a principal component analysis study.

OBJECTIVES: To contribute to the definition of external and internal limits of mixed states and study the place of dysphoric symptoms in the psychopathology of mixed states. METHODS: One hundred and sixty-five inpatients with major mood episodes were diagnosed as presenting with either pure depression, mixed depression (depression plus at least three manic symptoms), full mixed state (full depression and full mania), mixed mania (mania plus at least three depressive symptoms) or pure mania, using an adapted version of the Mini International Neuropsychiatric Interview (DSM-IV version). They were evaluated using a 33-item inventory of depressive, manic and mixed affective signs and symptoms. RESULTS: Principal component analysis without rotation yielded three components that together explained 43.6% of the variance. The first component (24.3% of the variance) contrasted typical depressive symptoms with typical euphoric, manic symptoms. The second component, labeled 'dysphoria', (13.8%) had strong positive loadings for irritability, distressing sensitivity to light and noise, impulsivity and inner tension. The third component (5.5%) included symptoms of insomnia. Median scores for the first component significantly decreased from the pure depression group to the pure mania group. For the dysphoria component, scores were highest among patients with full mixed states and decreased towards both patients with pure depression and those with pure mania. CONCLUSIONS: Principal component analysis revealed that dysphoria represents an important dimension of mixed states.

[Validation of the QFS measuring the frequency and satisfaction in social behaviours in psychiatric adult population]. / Validation du Questionnaire de fonctionnement social (QFS), un autoquestionnaire mesurant la fréquence et la satisfaction des comportements sociaux d'une population adulte psychiatrique.

INTRODUCTION: Although everyone working in routine mental health services recognizes the scientific and ethical importance to ensure that treatments being provided are of highest quality, there is a clear lack of consensus regarding what outcome domains to include, what measure of assessment to use and, moreover, who to question when assessing. LITERATURE FINDINGS: Since the fifties, social functioning is considered as an important dimension to take into account for treatment planning and outcome measuring. But for many years, symptoms scales have been considered as sufficient outcome measures and social functioning improvement expected on the basis of symptoms alleviation. As symptoms and social adjustment sometimes appear relatively independent, no accurate conclusion concerning the patient's social functioning can so be driven on the basis of his clinical symptoms. More attention has then been directed toward the development of instruments specifically intended to measure the extent and nature of social functioning impairments observed in most psychiatric syndromes. Many of these instruments are designed to be completed by caregivers or remain time consuming and difficult to use routinely. Presently, in clinical practice, there is a need to rely on simple and brief instruments considering patients'perspective about their social adjustment as a function of time. AIM OF THE STUDY: The aim of this study is to present a new instrument, the QFS, initially developed in order to assess social functioning in patients involved in group psychotherapy programs conducted in a specialist mental health setting, as well as its psychometric characteristics. METHODOLOGY: It was designed to be completed in less than 10 minutes and the questions are phrased in a simple and redundant way, in order to limit problems inherent to illiteracy or language comprehension. The QFS is a 16 items self-report instrument that assesses both the frequency of (8 items) and the satisfaction with (8 items) various social behaviours adopted during the 2 weeks period preceding the assessment. It yields three separate indexes of social functioning, defined a priori and labelled "frequency", "satisfaction" and "global". The higher the scores, the better the social functioning. The QFS was administered to 457 subjects, aged between 18 and 65, including 176 outpatients (99 with anxious or depressive disorders, 25 with personality disorders and 52 with psychotic disorders) and 281 healthy control subjects. RESULTS: No significant difference was found between patients and controls according to age or gender distribution. Acceptance rate was high (>95%). Moreover, the QFS was generally acceptable to the clinicians who used it. Internal consistency calculated for each index ranged from 0.65 to 0.83 (Cronbach alpha). Test-retest reliability, calculated within a 15 days time interval on a sample of 49 healthy controls, ranged from 0.69 to 0.71 (intraclass correlation coefficient). Discriminant validity was calculated on healthy controls and patients divided into sub-groups according to their diagnosis. It showed to be excellent, with significantly higher scores in control subjects than in psychiatric patients and significant differences across diagnostic categories (Kruskal-Wallis ANOVA with post-hoc tests, all p<0.05). The convergent validity of the QFS with other measures of social functioning was calculated, using the Social Adaptation Self-Evaluation Scale (SASS) and the Social Adjustment Scale Self-Report (SAS-SR). With the SASS, the convergent validity was higher among patients (Spearman rS 0.71 to 0.92, p<0.01) than controls (rS from 0.49 to 0.66, p<0.001). In healthy controls, correlation with the SAS-SR was moderate but statistically significant (rS from - 0.21 to - 0.44, p<0.05). When comparing QFS scores with self-rated symptoms severity, lower levels of social functioning were significantly associated with more severe symptoms according to the Brief Symptom Inventory (BSI: rS from - 0.38 to - 0.65, p<0.001). The QFS indexes demonstrated sensitivity to change (Wilcoxon: all p<0.05) on a sample of 27 out-patients suffering from anxious-depressive disorders questioned before and after 4 months of cognitive behavioural group therapy running on a weekly basis during 16 sessions of 2 hours each.The factorial validity of the QFS was measured through 3 separate factor analysis conducted using the data of 457 subjects. The first analysis considered only Frequency items; 7 out of 8 items had loadings above 0.5 on Factor 1 accounting for 30.7% (unrotaded) of the variance. The second analysis considered only Satisfaction items; all items had loadings above 0.6 on Factor 1 explaining 43.4% (unrotaded) of the variance. And finally, in the third factor analysis, all QFS items were included; 15 out of 16 items had loadings above 0.4 on Factor 1 accounting for 30% (unrotated) of the variance. Concerning the factorial validity of the instrument, these results suggest that all QFS items belong to the same underlying dimension. DISCUSSION: Finally, provisional norms for the QFS are provided for healthy controls, in order to characterise individual patients or patient subgroups. In conclusion, the need for assessment in clinical routine, in order to estimate different aspects of patients conditions as well as the quality of the treatment provided, has contributed to the development of a large variety of instruments measuring several domains. Concerning the level of social functioning, many instruments fail to meet chief criterion of feasibility, remaining often too complex or time onsuming. Moreover, only few of them are available in French. CONCLUSION: The QFS presented here is a brief, simple and easy to administer self-rating scale that displays satisfactory psychometric properties. It seems to be a valuable instrument for the monitoring of social functioning in psychiatric patients which, from a therapeutic point of view, may have a clear impact as it sets up expectation of change and allows both to reality test patients and therapists beliefs about the presence of progress or not and to identify if therapy is working on this specific outcome domain. Though, to date, the administration of the QFS to other populations and treatment modalities requires further investigation.

A stepwise drug treatment algorithm to obtain complete remission in depression: a Geneva study.

QUESTIONS UNDER STUDY/PRINCIPLES: We describe the proportion of severely depressed outpatients reaching complete remission at the different stages of a drug treatment algorithm. We compare several treatment options for SSRI (selective serotonin reuptake inhibitor) non-responders and test the feasibility of the algorithm in clinical conditions. METHODS: Patients with severe depressive disorders (ICD-10; MADRS > or = 25) admitted to an academic outpatient clinic were enrolled in this algorithm-guided sequential treatment protocol (starting with an SSRI and ending with a tricyclic, lithium, triodothyronine combination). The general principle of the algorithm was to boost the drug therapy in the event of non-response. RESULTS: 135 patients entered the study and 131 were eligible for analysis. From this group, 86 patients dropped out (65.6%), 40 reached complete remission (30.5%) and 5 patients did not reach remission at all (3.8%). In the 117 patients to whom a last observation carried forward approach was applied, the median improvement of the MADRS score was 48.0% (range -20.7%-100%), with 48.7% of patients considered responders, 23.1% partial responders and 28.2% non-responders. Median retention time was 8 weeks (range 2-34). CONCLUSIONS: This algorithm-guided antidepressant treatment was acceptable for clinicians and resulted in an elevated final response rate among study completers. However, the dropout rate was high, mainly due to treatment interruption or non-observance.

Olanzapine plasma level in relation to antimanic effect in the acute therapy of manic states.

The aim of this study was to evaluate internal as well as external validity of the two most frequently used mania scales, the Young Mania Rating Scale (YMRS) and the Bech-Rafaelsen Mania Scale (MAS), in patients with DSM-IV mania. Mokken analysis was used to evaluate internal validity in which a coefficient of homogeneity of 0.40 or higher indicates that the total score is a sufficient statistic. The external validity was evaluated by plasma-level relationship of olanzapine. In total, 20 patients with DSM-IV mania were analysed, and the coefficient of homogeneity was acceptable for the MAS, but not for the YMRS. In a subgroup of females who over 2 weeks had received a fixed dose of 20 mg olanzapine daily, a significant association was found between MAS scores and plasma levels, but this association was not obtained with the YMRS. In conclusion, the MAS was found superior to the YMRS in regard to both internal and external validity.

A novel water-soluble cyclosporine A prodrug: ocular tolerance and in vivo kinetics.

The purpose of this study is to demonstrate that a novel water-soluble prodrug of cyclosporine A (CsA) intended for topical ocular administration, does not induce eye irritation in a rabbit model and is able to generate therapeutic concentrations of CsA in the precorneal area immediately after administration. The eye irritancy of the prodrug and CsA control solution was assessed by the Draize test and by confocal laser ophthalmoscopy (CLSO). Residence time and tear concentrations of prodrug and CsA in the rabbit eye were assessed by HPLC. The Draize test showed an excellent tolerance for the prodrug solution while the reference CsA oil solution induced lachrymation and irritation. The CLSO-measured corneal lesions, subsequent to treatment with the prodrug and reference solutions, were 3% and 9%, respectively. The prodrug transformed rapidly, leading to relatively stable CsA concentrations in tears with a maximal concentration of 94 microg ml(-1) over the observation period. This study demonstrated that the prodrug solution was well tolerated and that clinically significant CsA tear concentrations were achieved. UNIL088 is a promising molecule in the treatment of immune-related disorders of the eye.

[Translation and validation of a French version of the Young Mania Rating Scale (YMRS)]. / Traduction et validation française de l'échelle de manie de Young (YMRS).

Both the Young Mania Rating Scale (YMRS) and the Mania Assessment Scale (MAS) have been widely used during the last decade for the evaluation of severity of mania in clinical trials. For both scales good inter-rater reliability, validity and sensitivity to change have been reported. The French version of the MAS has been validated. To our know-ledge, the YMRS has not yet been translated into French and validated. The main objective of the present study was to validate a French version of the YMRS and to test its use in manic patients entering a study on the effectiveness of valproic acid and olanzapine combination. After translating the items in French, we tested this version of the YMRS on two samples of psychiatric patients recruited in a ward of adult inpatients (18 to 65 Years old) at the Department of Psychiatry, Geneva University Hospital. The first sample included 18 (hypo) manic inpatients (10 males, 8 females). Mean age was 37.0 (standard deviation 10.1). Interviews were video taped and assessed by three different judges on both scales (YMRS and MAS). The second sample included 20 inpatients (5 males, 15 females) who provided written informed consent to enter a study on the association of valproic acid and olanzapine in the treatment of mania. Mean age was 40.0 (standard deviation 11.3). Patients were followed over four weeks and assessed on both scales (YMRS and MAS) every seven days (day 0, 7, 14, 21 and 28). On day 7, patients were assessed during a joint interview by two of three judges who independently administered both scales in permuted order. On days 0, 14, 21 and 28, patients were evaluated by one of the same three raters. Inter-rater reliability was assessed by comparing item scores and total scores assigned by different judges with intra-class correlation coefficient ICC (2,1). Three judges were considered for patients in sample 1. Two judges were considered for patients in sample 2 (day 7 assessment). Concurrent validity with the MAS was analysed in sample 2 on days 0, 7, 14, 21 and 28 using Spearman rank-order correlation coefficient. Sensitivity to change was assessed in sample 2 by comparing total score at inclusion and at last observation using Wilcoxon signed ranks test. For both the MAS and YMRS, intraindividual change was calculated as the difference between total scores at inclusion and discharge (last observation carried forward approach). The relationship between changes on the two scales was analysed through Spearman correlation coefficient. Significance level was set to 0.05 for each test. Ranges of YMRS total scores were 2 to 32 in sample 1 and 1 to 28 in sample 2, indicating symptom severity from euthymic to moderately manic. Inter-rater reliability was very good for the total scores in both samples, both for the MAS and the YMRS (ICC>0.89). When considering YMRS individual items, correlation coefficient varied from 0.61 to 0.96 in the first sample. In the second sample, 9 of 11 items displayed values above 0.63. The remaining two items, increased motor activity and energy and Language-thought disorder, presented modest inter-rater reliability (ICC=0.54 and 0.50 respectively). This was largely attributable to a single patient, who was perceived very differently by the two judges (scores 0-2 for increased motor activity and energy; 1-4 for Language-thought disorder). When this patient was excluded, intra-class correlation coefficients were above 0.69 for both items. Overall, inter-rater reliability of the YMRS items was in the same range as for the MAS items (0.61-0.96 vs 0.61-0.93 in sample 1; 0.50-0.93 vs 0.54-0.83 in sample 2). Correlation between the two instruments was very high and statistically significant at each weekly assessment (rs>0.91, p<0.001) except for day 21 which displayed a somewhat lower correlation (rs=0.75, p<0.01). This latter result was attributed to a reduced spread of values and number of patients on day 21. YMRS and MAS total scores as a function of time in patients receiving combined treatment with olanzapine and valproic acid (sample 2) show that for both at for both scales, total scores significantly decreased from day 0 to last observation (Wilcoxon signed ranks test, p<0.001), with median decrease of 18 points both on the YMRS (range 9-32) and MAS (range 10-33). Median relative decrease was 67% for the YMRS and 69% for the MAS. When analysing the relationship between intraindividual changes on the YMRS and MAS, highly significant correlation was observed (Spearman rs=0.93, p<0.001), showing that the two scales were virtually interchangeable in assessing treatment efficacy. In conclusion, the YMRS is a simple and easy-to-use instrument for measuring severity of manic symptoms The newly translated French version was satisfactory in terms of inter-rater reliability, concurrent validity with the MAS, and sensitivity to change in patients receiving treatment for manic symptoms. This should allow its future use for international comparison studies.

Therapeutic drug monitoring databases for postmarketing surveillance of drug-drug interactions.

Drug-drug interactions can be associated with patient morbidity due to either increased toxicity or a potentially ineffective concentration. Because interactions cannot always be anticipated during drug development and actual patients receiving a drug for therapeutic use often differ from those included in clinical trials, postmarketing surveillance is essential. Therapeutic drug monitoring (TDM) databases offer a unique opportunity in this respect. Prerequisites for TDM databases to provide valid information in a pharmacoepidemiological perspective include the following: precise description of exposure to the potentially interacting drugs; measurement of parent compound and active metabolites through accurate and precise analytical techniques; documentation of relevant patient characteristics that may act as confounding factors (e.g. gender, age, smoking habits); repeated assessments over time if possible; and sound pharmacokinetic framework for data selection, analysis and interpretation. The contribution of TDM to the documentation of drug-drug interactions takes advantage of different possible study designs, discussed on the basis of recently published studies. The single case report plays an important role as an alert signal. It is illustrated for a patient on long-term treatment, who displayed an unexpectedly high clozapine concentration after the introduction of ciprofloxacin comedication. The prospective on and off comedication panel study shows advantages in terms of carefully selected inclusion criteria and control of treatment modalities. A study of the thioridazine-fluvoxamine interaction is presented, with patients followed on thioridazine monotherapy, after introduction of fluvoxamine and after its discontinuation. The main advantage of the retrospective large-scale TDM database screen is representativeness of patients actually treated, whereas drawbacks are related to quality of data and suitability for valid interpretation. Such an approach is illustrated by a review of data collected over 10 years of routine TDM that allowed documenting induction of nortriptyline metabolism by carbamazepine and inhibition by several phenothiazines. Finally, population pharmacokinetics is well suited to observational data collected for TDM purpose, provided quality is ascertained. Focus is placed on interindividual variability and relationship between pharmacokinetic parameters and patient characteristics, including comedication. The population approach is discussed with respect to a study that documented a 32% increase of haloperidol clearance associated with anticonvulsant comedication, in addition to effects of age and bodyweight. Among factors to consider for improved effectiveness in the use of TDM databases for postmarketing surveillance of drug-drug interactions, integration of efficacy and safety data in future studies and communication of expert recommendations to prescribing physicians are essential.

Population pharmacokinetics of clomipramine, desmethylclomipramine, and hydroxylated metabolites in patients with depression receiving chronic treatment: model evaluation.

Because metabolites play a major role in the clinical response to clomipramine, the objective of the current study was to develop a population model and evaluate its performance to describe the pharmacokinetic profiles of clomipramine (C) and its active metabolites desmethylclomipramine (DC), 8-hydroxy-clomipramine (OHC) and 8-hydroxy-desmethylclomipramine (OHDC). A first sample of 14 patients served for development of a 2-molecule C and DC model, which was shown to provide reasonable estimates of AUC-based clearances, as well as precise estimation of interindividual variability. Simulated data, generated to mimic a semi-rich sampling design and chronic treatment with clomipramine, indicated that clearance estimation was feasible under routine treatment conditions. A second sample of 30 patients, recruited prospectively and followed for a median 4-week period, was used to extend the 2-molecule model to a 4-molecule model. Goodness-of-fit assessment revealed that model-predicted concentrations were reasonably close to observed concentrations for a majority of patients. Interindividual variability was 50% to 60% for hydroxylation and desmethylation clearances, and residual variability was 30%. The proposed model incorporates much of what is known about the metabolism of clomipramine and may valuably integrate the influence of genetic and environmental factors on each metabolic pathway.

Modelling during drug development.

With the advancement of both biological and computer sciences, new drug development faces the challenge to integrate a huge amount of knowledge accumulated from the very early quantitative structure-activity relationship investigations of the candidate molecule to the large scale clinical trials in patients. Whereas pharmacokinetics and pharmacodynamics are fields in which modelling has long demonstrated its value, its potential in many other areas of drug development has recently been the object of intensive scientific activity. The present review places emphasis on these newer applications; it includes the opinion of many experts in often highly specialised areas such as in vitro to in vivo extrapolation, toxicokinetics, non-continuous response models, population approaches and computer assisted simulation of clinical trials. It is most probable that in the near future many of these areas of research will be the objects of intensive and interesting developments. This will undoubtedly lead to improve developmental strategies for new drugs as well as more individualised pharmacological strategies for patients.

Development of validated stereoselective methods for methadone determination in clinical samples.

A stereoselective analysis of methadone (Mtd) in whole blood and serum was developed using liquid chromatography on a protein based chiral stationary phase. Liquid-liquid extraction (LLE) and solid phase extraction methods were applied before chromatographic analysis. The extraction procedure, as well as the choice of the biological matrix, showed significant differences in the extraction yield and in the precision of the assays. Serum was selected for this assay and LLE was chosen as the preparation step because of its simplicity and rapidity. The total procedure was validated and applied to clinical samples. Samples taken from 45 heroin-addicted patients were analyzed. A correlation was found between the dose administered and Mtd concentration (total and R-form), but interindividual variability of the total normalized Mtd was seen (concentration varied from 90 to 530 ng/ml). Furthermore, two populations were apparently observed with a mean Mtd concentration of 200 and 475 ng/ml, respectively. Stereoselective analyses showed that more than 50% of the patients presented a nonracemic ratio, and particularly about 25% showed a preferential metabolism of the active R-Mtd enantiomer. Therefore, the stereoselective determination of Mtd is necessary to improve the quality of the treatment of heroin addiction.