Therapeutic drug monitoring of risperidons: New insight into variability factors

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dosage-). When comparing the survival experience of TD cases and controls over the total follow-up time by the log-rank test the results were non significant (x2 = 1.94, d.f. = 1,p = 0.16) but it changed when focusing on TD severity (x2 = 6.83, d.f. = 2, p = 0.03). This finding is explained by the excess of mortality experienced in the moderate plus severe TD patients (16 deaths observed vs. 9.5 expected). Our results agree with former research (McClelland et al., 1986), point to the consideration of TD as a life threatening factor and to the importance of the TD severity assessment. References

[II Andia, I., Zumarraga,M., Zabalo, M.J., Bulbena,

A., and Davila, R. (1998) Differential effect of haloperidol and clozapine on plasma homovanillic acid in elderly schizophrenic patients with or without tardive dyskinesia. Biol Psychiatry 43, 20-23. PI Caligiuri MI’., Lacro J.P., Rockwell E., McAdams L.A., and Jeste D.V. (1997) Incidence and risk factors for severe tardive dyskinesia in older patients. Brit J Psvchiat 171. 148-153. [31 Mcdlelland H.A., Dutta D., Metcalfe A., and Kerr T.A. (1986) Mortality and facial dyskinesia. Btit J Psychiat 148, 3 10-3 16.

[p.2.028( Onset of action in acute schizophrenia, amisulpride versus haloperidoi S. Turjanski’, W. Rein’, M. Theron2. ‘Synthdlabo Groupe, 92350 Le Plessis-Robinson:

2SynthtYabo Recherche, 92200 Bagneux, France

Positive symptoms of acute schizophrenia are well treated by antipsychotics. An interval of 15 to 20 days is expected before the beginning of the therapeutic effect. Nevertheless, the delay in the response remains an important issue in the evolution of these patients. Amisulpride, an atypical antipsychotic with a selective high affinity for the dopamine D2 and D3 receptors, preferentially in limbic areas, has shown efficacy either in acute schizophrenia at high doses (400 to 1000 mg/d) and in predominant negative symptoms at low doses (100 to 300 mg/d). The onset of action in acute patients was analyzed in 2 double-blind studies comparing amisulpride (400 to 800 mg/d) with haloperidol (15 to 20 mg/d). Methods: Patients had to fulfill DSM III-R criteria of schizophrenia with acute exacerbation, parandid, undifferentiated and disorganised type. In addition, they had to have a minimal score on the BPRS psychotic cluster to be included. Patients were considered as responders if they had a substantial decrease of at least 50% of the BPRS total score from baseline at the end of the first week of treatment or after two weeks. Chi2 test was used to compare treatment groups. Results: In study 1, 125 patients were treated with amisulpride 400 and 800 mg/d and 61 patients with haloperidol. In study 2, 94 patients were treated with amisulpride and 94 with haloperidol. In the first study, at day 7, 18% of responders to amisulpride versus 5% to haloperidol was observed (p = 0.016). In the second study, 28% of amisulpride patients were responders versus 14% of haloperidol patients (p = 0.022) at the end of the second week of treatment. When both studies were pooled given their similar design, responders on amisulpride were statistically significant superior compared with haloperidol (13% and 4% respectively) (p = 0.003) at day 7 and at day 14 (38% vs 24%; p = 0.004). Conclusion: In the challenging treatment of acute schizophrenia, amisulpride have shown an important reduction of 50% of symptoms after one and two weeks of treatment. Onset of action was statistically significant superior after one and two weeks of treatment with amisulpride compared with a standard antipsychotic such as haloperidol.

IP.2.029] E,:‘W;

of weight gain during olanzapine

B.J. Kinon, B. Basson, K. Szymanski, G.D. Tollefson. Lil& Research Labomtories,

Eli Lilly and Company, Indianapolis,

IN USA

Objective: Predictors of weight gain in olanzapine-treated patients diagnosed with schizophrenia, schizoaffective, or schizophreniform disorders were analyzed retrospectively in a large, multicenter clinical trial. Method: Data from patients treated with either olanzapine or haloperido1 in a single, multi-center trial were analyzed post hoc using an analysis of variance (ANOVA) model. Ten clinically relevant covariants showed significant ability to predict weight gain within olanzapinetreated patients, including appetite, clinical response (percent reduction in the baseline Brief Psychiatric Rating Scale (BPRS)), baseline Body Mass Index (BMI), dose, age, gender, geographic region, observation time within interval, alcohol use and smoking. The analysis was repeated at 6 weeks (N = 1295), 30 weeks (N = 1040), and 52 weeks (N = 626), and also for haloperidol-treated patients at the same timepoints. Results: The most significant predictors of olanzapine-associated weight gain, both statistically and in terms of magnitude of response, were an increased appetite, younger age, a positive clinical response, and a low baseline BMI. During the first 6 weeks, patients reporting excessive appetite gained more than those having unchanged appetites (3.69 kg vs. 1.80 kg; p < ,001); younger patients gained more than older patients (2.40 kg vs. 1.32 kg; p < .003); those with the greatest reduction in baseline BPRS gained more than those with the least improvement (2.54 kg vs. 0.86 kg; p < ,001); low baseline BMI patients gained more than high baseline BMI patients (2.15 kg vs. 1.86 kg; p i ,017). These relationships were similar at the 6, 30, and 52 week time points. The magnitude of weight gain at 52 weeks of treatment suggested a considerable slowing of the rate at which weight was gained relative to the first 6 weeks of treatment. A mean dose of 7.5 mg or less was found to produce less weight gain in the tirst 6 weeks, though this effect was no longer significant at 30 or 52 weeks. Smoking, alcohol use, and gender all had statistically significant though clinically less important effects on weight gain (less than 1 kg difference at 6 wks). Haloperidoltreated patients as a group did not experience significant weight change. Across individual patients, though, similar factors as with olanzapine were predictive of haloperidol-associated weight gain including increased appetite, younger age, a low BMI, and a positive clinical response. Only 4 olanzapine-treated patients (0.3%) discontinued treatment due to weight gain during the 52 week period (vs. 0% on haloperidol). Conclusions: The significance levels of a variety of factors tested in a statistical model support the idea that olanzapine-associated weight gain is multifactorial in nature. Controlling appetite behaviors and promoting healthy lifestyle options for schizophrenic patients may be indicated as a way to deal with this weight gain. The association between weight gain and improved clinical response, as demonstrated with olanzapine as compared with haloperidol, may suggest that weight gain is mechanistically associated with the greater efficacy of novel antipsychotic drugs, although further investigation is required to define this relationship.

Ip.2.0301 Therapeutic drug monitaring of risperidone: New insight into variability factors A.E. Balant-Gorgia’M. , Gex-Fabty2, L.P Balang. ‘Therapeutic Drug Monitoring Unit: ‘Clinical Research Unit Department of Psychiatry, Geneva Uniuersity Hospitals, Geneva, Switzerland The pharmacology and pharmacokinetics of risperidone have been extensively reviewed. The biotransformation of risperidone to O-hydroxyrisperidone, its major active metabolite, is under the control of the polymorphic CYP2D6 enzyme. Factors that have been shown to influence plasma concentrations include CYP2D6 metabolising capacity, age, impaired renal and hepatic functions, possibly gender, and comedication that inhibits CYP2D6 dependent metabolism. There is an enormous gap, however, between premarketing studies in physically healthy subjects

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with an unambiguous diagnosis of schizophrenia and performance of the drug in routine clinical practice. The present study was thus aimed at investigating variability factors in a broader population and under various prescription patterns representative of actual clinical practice. It included 92 patients (37 males and 55 females) who received risperidone orally and had at least one concentration measured at steadystate. Median age was 41 years (range I7-91), with 27% of patients 2 70 years old. Posology was selected by the attending psychiatrist and ranged from 0.5 to 11 mg per day. Median concentrations of risperidone and metabolite 9-OH-risperidone were 2.2 ngiml (range 0.5-52.5) and 18.4 ng/ml (range 5.6-95.0) respectively. Dose normalised concentrations were analysed for the influence of covariates using multiple regression analysis. Whereas variability in patients was impressive for risperidone, it remained relatively modest for 9-OH-risperidone, with 105 and 17 maximum to minimum ratios respectively. A first insight into raw data revealed that elderly patients generally administered 1 to 2 mg per day reached concentrations of the active moiety (i.e. sum of parent compound and metabolite) in the range of values obtained for younger adults prescribed 4 to 6 mg per day. Median risperidone to 9-OH-risperidone ratio was 0.12 in the population, with 9 patients displaying ratios above unity, among whom 2 patients had received SSRI comedication. When considering linear models, age was identified as a major source of interindividual variability, with expected increases of 340% and 220% for concentrations of parent compound and metabolite with age increasing from 20 to 80 years (p < 0.001). Body weight provided an additional significant contribution to the variability of 9-OH risperidone concentration, with a 20 kg higher body weight associated to a 23% concentration decrease (p < 0.001). It cannot be ruled out, however, that gender may have acted as a confounding factor in such an observation. SSRI comedication was significantly associated with elevated concentrations of parent compound (p < 0.005), in keeping with an inhibitory action on CYP2D6 isoenzyme. Biperiden provided an additional significant contribution, although minor, to 9-OH-risperidone variability (p < 0.05): patients with elevated concentration to dose ratios may have been more likely to suffer from extrapyramidal symptoms and, as a consequence, to be prescribed anticholinergic medication. The recommendation to consider a dose reduction and a careful dose titration in the elderly carries additional relevance in actual clinical practice, when older age is often associated to somatic diseases and comedication considered as exclusion criteria in formal pharmacokinetic studies.

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Reiiability and validity of the Greek version of the Calgary depression scale for schizophrenics

V Kontaxakis, B. Havaki-Kontaxaki, S. Stamouli, M. Margariti, K. Kollias, E. Angelopoulos, J. Jemos, G.N. Christodoulou. Department of Psychiatry, Uniuersity of Athens, Eginition Hospital, Ave., 11528 Athens, Greece

74 Vas. Sophias

The Greek translation of the Calgary Depression Scale (CDS) was used in consecutive schizophrenic patients, defined according to DSMIV criteria and hospitalized at the Eginition Hospital Department of Psychiatry, University of Athens, in order to assess some psychometric properties of the scale (reliability, validity). Twenty four patients (mean age 29.4 + 9.8 years) were included in the reliability study, while 88 patients (mean age 29.6 + 8.1 years) in the validity study. Reliability: Four steps were taken in the analysis of the reliability of the scale a. inter-rater reliability, b. test-retest reliability, c. split-half reliability, d. internal consistensy. The CDS was found to have a high inter-rater and test-retest reliability (r = 0.97, p < 0.0001, and r = 0.93, p < 0.0001, respectively) as well as split-half reliability (r = 0.97, p < 0.0001) and internal consistensy (r = 0.50-0.88, p < 0.02-0.0001) Validity: The CDS was compared to two established measures, Hamilton’s Depression Rating Scale (HDRS) and a depression measure derived from the Brief Psychiatric Rating Scale (BPRS-D). The CDS score had significant strong correlations with both the scores on the HDRS (r = 0.81, p < 0.001) and on the BPRS-D (r = 0.80, p < 0.001).

1

Conclusion: The Greek version of the CDS was found to have a high reliability and validity and can be a useful instrument for assessing depression in schizophrenics for both clinical and research aims. References [I]

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Addington D, Addington J, hlaticka-Tjmdale E. Assessingdepression in schizophrenia: The Calgary Depression Scale. Br J Psychiatry 1993; 163 (suppl.22): 39-44.

Treatment of clozapine-induced agranulocytosis with grenulocyte-colony-stimulating factor (G-CSF): Three cases

Leotsakou’St. , Theodoropoulou’ *I $ Baltathakis2, A. Giannakaki’, A. Kolovou2, S. Gigantes2, T. Karmins , E. Nikiforakis2. ‘Depurtment

C.

of Psychiatv; ‘Department of Hematology mos General Hospital, Athens, Greece

and Lymphoma, Evangelis-

Agranulocytosis [defined as an absolute neutrophil count (ANC) < 0.5 x 109/L] is the most severe adverse effect of clozapine. It has a cumulative incidence of 0.8% at 12 months in treated patients, lasts 14 to 22 days after discontinuation of treatment and bears a 34% mortality. The mortality rate in patients presenting with secondary infections due to agranulocytosis while still on clozapine can be as high as 50%. A more favorable outcome is seen with early recognition and prompt clozapine discontinuance. Timely administration of hematopoetic growth factors can shorten the duration of agranulocytosis thus decreasing mortality significantly. We report on three schizophrenic patients (1 woman/2 men; ages 2 1.45 and 46 years) who presented with agranulocytosis (ANC: 0.0, 0.08 and 0.30 x 109/L respectively) on the eighth week (n = 2) and the fifth year (n = 1) of clozapine treatment. Two of the patients also developed high fever. The hemoglobin and platelet values were within normal range. Review of bone marrow smear in 2 patients confirmed complete absence of the myeloid series. The patients were managed with the early (less than 48 hours since admission) administration of granulocyte colony stimulating factor (GCSF) and broad spectrum antibiotics after discontinuing clozapine. ANC rose to > 0.5 x 109/L on the 5& (n = 1) or 6th (n = 2) and to > 1.0 x 109/L on the 7th day of treatment. G-CSF was discontinued after ANC remained > 1.0 x log/L for three consecutive days, Treatment with G-CSF can dramatically shorten the duration of clozapine-induced agranulocytosis even in the most severe cases characterized by profound depression of the myeloid series in the bone marrow. Serial neutrophil count measurements in patients receiving clozapine are mandatory. Prompt administration of G-CSF when ANC decline to < 1.0 x 109/L, can possibly decrease the morbidity associated with severe agranulocytosis. A high index of suspicion is invariably required because agranulocytosis can occur even 5 years from the commencement of clozapine treatment,

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The effect of novel antipsychotics clozapine, olanzapine and risperidone in rat oral dyskinesia and working memory

H. Rosengarten, D. Quartermain, A.J. Friedhoff. New York School oj Medicine, Department of Psychiatry, Millhauser Laboratories, New York, USA The effect of Dl agonist SKF38393 and 5-HTlC agonist m-CPP on

repetitive jaw movements (RJM) was studied in rats. Acute administration of SKF38393 and/or m-CPP induced RJM in a dose dependent manner. In rats treated with both drugs, RJM responses were about equal to the sum of those obtained with each drug alone. The induction of RJM by SKF38393 was somewhat lower in rats pretreated with 5-HTzC receptor antagonist, mianserin, whereas mianserin reduced severely RJM induced by m-CPP alone. Dl antagonist SCH23390 inhibited SKF38393 induced RJM whereas it had no effect on m-CPP induced chewing