Risperidone in the treatment of rapid cycling bipolar disorder

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P.I Affective disorders and antidepressants

a few hours, In conclusion, the new antidepressant minazapine offers cliniciansan effectiveand safe option for treatingall types of depression. Reference

van Moffaert M,de Wilde J, Vereecken A, Dierick M, Evrard JL, Wilmolle and Mendlewicz 1. Mirtazapine is more effective than trazodone: a double-blind controlled study in hospitalized patients with major depression. International Clinical Psychopharmacology 1995; 10: 3-9.

I P.1.0121 Pharmacokinetics andrelevance for choice L.P.C.Delbressine. Department of DrugMetabolism and Kinetics, N. V. Organon, P.O. Box 20,5340 Oss, TheNetherlands Preclinicalstudies of CNS-activedrugs can provide information on potential interactions, both at a phannacokinetic and pharmacodynamic level. For the interpretation of pharmacodynamic interactions, it is necessaryto evaluate the contribution of parent compound as well as metabolites to the overall phannacodynamic profile. Preclinical in vitro data can also provide information on possible interactions with other drugs and their clinical relevance. These data are usuallyobtainedin in vitroexperiments with liver homogenates and hepatocytes, Furthermore, data on relationship between plasma levels and brain concentrations in animals may be of help for extrapolation to man based on human plasma data. Mirtazapine has a linear pharmacokinetics within dose range of 15-80 mg. It is rapidly and well absorbed from the gastrointestinal tract after single and multiple dosing, and peak plasma levels are reached within 2 hours [I). The absolute bioavailability is approximately 50% [2]. The presence of a fatty meal has no effecton the rate and extension of absorption of rnirtazapine. It's half life of 2D-40 h justifies once daily dosing, and results in attaining a steady-state within 3-5 days. Approximately 100% of the orally administered dose is excreted via urine and feces within 4 days. Mirtazapineis extensively metabolized in the liver. The main pathways of biotransformation are demethylation and oxidation, followed by conjugation. In animal studies, the only pharmacologically activemetabolite demethyl-mirtazapine is shown to be approximately lO-fold less active than the parent compound. Preclinical data consistently show that rnirtazapine has a very low potential for clinically relevant interactions with other drugs. Its binding to plasma proteins is relatively low and aspecific. Furthermore, rnirtazapine appears to have no inducing or inhibiting effects on the hepatic cytochrome P450 system and disposition independent of polymorfic CYP2D6 activity. References

TImmer C,J., Lohmann A.A.M. and Mink C.P.A. (1995) Pharmacokinetic dose proportionality study at steady sate of mirtazapine from Remeron tablets. Human Psychopharmacology 10 (suppI2): S97-S106. [21 Voortman G. and Paanakker J.E. ( 1995) Bioavailability of mirtazapine from Remeroo tablets. Human Psychopharmacology 10 (supp12): S81-S96. [1]

IP.1.013! Mental retardation: Effectiveness of fluvoxamlne in the treatment of depressive symptoms: Case reports

A. Lenzi, T.E Rastelli I, I. Bianco, cr, Gianfranchi 1. Istituto di Psichiatria- Universita degliStudidi Pisa Vza Roma, 67, 57100, PlSA; I Centro Provinciale di Riabilitazione A.I.A.S.- Pistoia The anomalies due to mood disorders in mental retardation represent a diagnostic problem not easy to solve, because of the poorness of symptoms (usually limited to cry crises, self and external aggressivity, anger crisis), caused by the insufficient expressive capability of these subjects. In the daily practice these anomalies are usually considered as psychotic excitement episodes, and are treated with neuroleptics. These drugs provoke high sedation, worse the already compromised motorial capabilities of these patients, and slow down the rehabilitation and therapeutic processes. In the Centro Provinciale di Riabilitazione A.IAS . di Pistoia (Italy) t1uvoxamine has been used in these patients 100 mglday associated when necessary with antiepileptics and thymoleptics in those cases in which

the treatmentwith neuroleptics or other antidepressants did not showany effectivenes, Treatment has been administered to 8 patients (5 male and 3 female), aged betweeen 21 and 55; 4 of them are affected by severe oligophrenia due to encephalopatia praecox, 2 by Down's Syndrome, 1 by autism, 1 by familiar oligophrenia. The diagnoses for which fluvoxamine treatment was taken into consideration were: reactive depression (4 cases), depression in bipolar disorder (2 cases), panic attack with agoraphobia (l case), not motivated anger crisis (2 cases). Fluvoxamine has shown effectivein 6 cases, with a latency inferior to 15 days. No manic switch has been observed in the 2 bipolar patients in a period of 6 monthsof treatment. During the observation period (currently between 2 and 30 months) no side effector relapses have been seen. Two cases (anger crisis) did not respond to the treatment the first (affected by autism)didn't show any improvement at all, while the second (familiar oligophrenia) showedan early improvement which disappeared within a few weeks. In this clinical observation (which should be confirmed with further controlled studies),fluvoxamine showedgood tolerabilityand prompt efficacy in those syndromes which includedPanic Attacks and Depression, while it was not effective in those cases for which the treatment choice was induced by the failureof other treatments. It must be underlined the necessityof an accurate diagnosis, based not only on the clinical outcomes (usually insufficiet to make a diagnosis according to the common criteria), but also getting infonnation from the relatives about stressful events in the patients' life: this can allow the doctor to get closer to patients' sufference in spite of the uniformity of the shownsymptoms. Reference

Vitiello, B., Behar, D.: Mental Retardation and Psychiatric illness (1992) Hosp Com Psych, 105-115. I P.1.014 1 Risperidone in the treatment of rapid cycling

bipolar disorder E. Viera, C. Gasto, A. Otero, 1. Vallejo. Clinic Barcelona, Department of Psychiatry, University of Barcelona, Villarroel 170, 08036Barcelona, Spain

Introduction: Risperidone is a benzisoxazole derivative that combines potent 5-JIT2 antagonism with D2 antagonism, with contrasted antipsychotic activity. Although its efficacy in treating psychotic symptoms of schizophrenia is well-documented, we still lack controlled clinical trials on its possible therapeutic role in affective disorders, such as mania, psychotic depression, schizoaffective disorder, and rapid cycling bipolar illness. Preliminary observations of our own (Vieta et al, in press) suggested that risperidone could be useful in the treatment of dysphoric maniaand mixed bipolar disorder, even in the absence of psychosis. This encouraged us to conduce an open trial on the efficacy of risperidone in the treatmentof the more severe forms of bipolar illness, including rapid cycling. To our knowledge, there are no previous reports on the treatment of such disorder with risperidone. Method: We conducted an open-label pilot study of risperidone in the treatment of rapid cycling bipolar patients. We studied 10 patients with DSM-IV rapid cycling bipolar disorder who were refractory to lithium carbonate, carbamazepine and valproate. In spite of documented refractoriness, mood-stabilizing drugs prescribedprior to study initiation were maintained. Other drugs, like antidepressants or antipsychotics, were discontinued. If the patient was taking antidepressants, risperidone was initiated only when persistence of rapid cycling was verified after wash-out. All patients gave informedconsent. Bipolar disorder diagnosis was made using the Schedule for Affective Disorders and Schizophrenia (SADS). DSM-IV criteria were applied to specify the presence of rapid cycling. Efficacy was measured weekly with the use of the YoungMania Rating Scale (YMRS), the Hamilton Depression Rating Scale (HDRS), and repeated measuresof the SADS. Results: Eight of the 10 patients improved after the implementation of risperidone. Two patients dropped-out due to agitation and noncompliance, respectively. The number of episodes within 6 months after baseline was significantly lower than before baseline(p < 0.05 Wilcoxon

P.1 Affective disorders and antidepressants signed-rank test). Mean YMRS and HDRS scores were significantly lower after follow-up than at baseline (p < 0.01 t Student paired test). Mean risperidonedose was 3.2 mg/day. Discussion: Although Dwight et al (1994) reported an increase of manic symptoms in 6 bipolar patients treated with risperidone, preliminary data suggest that some atypical antipsychotic drugs, such as clozapine, may have not only antipsychotic effects, but also thymoleptic effects on schizoaffective and rapidly cycling bipolar patients (Suppes et al, 1994).The results of the present study seemto confirmthat risperidone could be a good choice in the treatmentof refractory rapid cyclingbipolar disorder. References

Dwight, M.M., Keck, P.E., Stanton, S.P., Strakowski, S.M., and McElroy, S.L. (1994) Antidepressant activity and mania associated with risperidone treatment of schizoaffective disorder. Lancet 344, 554--555. Suppes, T.,Phillips, K.A., and Judd, C.R. (1994) Clozapine trea~ent of.nonpsychotic rapid cycling bipolar disorder: a report ofthree cases. BiOI Psychiatry 36, 338--340. Vieta, E.,Gast6, C; andEscobar, R.Treatment ofdysphoric mania with risperidone. Human Psychopharmacology, in press.

IP.1.01SI Thesafety profile of fluvoxamine in elderly patients W. Wagner1, V. Hauser 2, L.F.Wong2. I Solvay Human Health Division, Hans Beckler Allee 20, Hannover 30173, Germany; 2 Solvay Pharmaceuticals, 901 SawyerRoad, Marietta, GA 30062, USA The safety profile of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine has been extensively assessed world-wide and information from 66 post-marketing studies conductedin 34,587patientshas recently been published (Wagner et al., 1994). This constitutes the largest collection of safety data ever presented for an antidepressant and clearly demonstratesthat fluvoxarnine is safe and well tolerated. The efficacy of fluvoxamine in the managementof depressionin elderlypatientshas been confirmedin a number of studies and evidence suggests that it is at least as effective as the tricyclic antidepressants whilst having a better safety profile (Tebbs and Martin, 1987; Wakelin, 1986),The safety profil~ of a drug is especially important in elderly patients who tend to be frail and suffering from coexistent conditions and are therefore more susceptible to age-related symptomsand side effects. The safety profileof fluvoxarnine has also been specifically assessedin the 4,843 elderly, mainly depressed patients (65 years or older; range 65 to 97 years) who were enrolled in the world-wide post-marketing studies. The daily dose of fluvoxamine ranged from less than 50 to 300 mg (the most common dose range was 100 to 149 mg which was given to 47.2% of patients) and the studies were conducted over periods of up to one year.The most conservative, or cautious,categorywas chosenthroughout the analysis in situations where more than one category was applicable. Overall, 3,250 patients (67.1%) completed the study period; adverse events accountedfor the discontinuation of 894 patients(18.5%). At least one adverse event was reported by 2,228 patients (46.0%), the most frequently affected body systems being the 'gastrointestinal' and 'nervous' systems. Nausea was the most common adverse event, occurring in 747 patients (15.4%), followed by somnolenceand asthenia, each reportedin 314 patients (6.5%). At least one serious adverse event was experienced by 135 patients (2.8%),hospitalisation being the most widespread classification (113 patients; 2.3%).Twenty-six patientsdied; none of the deaths were consideredto be related to fluvoxamine treatment. The incidence of overall suicidalitywith fluvoxamine was low (0.48%). In conclusion, the results from this extensive world-wide assessment of the safety profile of fluvoxarnine indicate that it is well tolerated in elderly patients and thus may be a good alternative to the tricyclic antidepressants, especially in this more vulnerable population. References

Tebbs VM, Martin AI. Affective disorders intheelderly: J,OOO patient GPtrial on new drug. Geriatric Medicine 1987; 17: 17-21. Wagner W, Zaborny BA, Gray TE. Fluvoxamine, A review of its safety profile in worldwide studies. International Clinical Psychopharmacology J994; 9: 222-226.

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Wakelin J. Fluvoxamine in the treatment of the older depressed patient; doubleblind, placebo-controlled data. International Clinical Psychopharmacology 1986; I: 221-230.

IP.1.016! Flu~oxamlne e~ective in preventing recurrence of major depresslon

I CHS Le Vinatier, Service d'lnjormation et d'Evaluation Medicale, 95 BlvdPinel, 69677 Bran Cedex, France; 2 Solvay Human Health, CJ van Houtenlaan 36, 1381 CP Weesp, The Netherlands

J.L. Terra I, F. Noel 2.

Although patients frequently experience recurrence of major depression, few studies have been conducted to investigate potential long-term preventative treatments. The selective serotonin reuptake inhibitor fluvoxamine has proven efficacy and safety in the long-term treatment of depression (Martin & Wakelin, 1986; Ottevanger, 1994) and evidence suggests that it may be effective in preventing recurrence (Franchini et aI., 1994).The aim of this double-blind, placebo-controlled, randomised, multicentre, parallel-group study wasto assess theefficacy of fluvoxamine in preventing recurrence of DSM-ill-R major depression. The study was divided into three phases. The first two phases were open and lastedfor 6 and 18 weeks, respectively. Only the responders(as assessedby the Montgomery-Asberg DepressionRating Scale [MADRS] and Clinical Global Impression [COlD were allowed to continue to the further phases (phase Il and Ill). Patients received fluvoxamine up to 300 mg/day during phase I, whilst the dosage was reduced to 100 mg/day during phase II. During phase ill, the patients were randomised to receive double-blind treatment with fluvoxamine 100 mg/day (n = 110) or placebo (n = 94) for a further 12 months. Patients were assessed monthly on the MADRS and at three-monthly intervals on the CGI and Covi anxietyscales. The incidence of recurrenee was significantly higher with placebothan with fluvoxamine (35.1 % vs 12.7%; P < 0.(01). Moreover, the time to recurrence was significantly longer in the fluvoxamine group than in the placebo group (181 vs 96 days; p = 0.005). Fluvoxamine was also significantly superiorto placeboin terms of the mean MADRS total score (7.8 vs 12.5; p < 0.001), COl severity of illness score (1.8 vs 2.4; p = 0.01) and Covi anxiety scale total score (4.7 vs 5.8; P = 0.002) at the end of the study. There was no difference betweenthe groups in the incidenceof adverse events(35%with fluvoxamine and 37% with placebo). The mostcommon events with fluvoxamine were headache (5%), abdominal pain (5%) and weightincrease(5%), whilst placebo wasmost frequentlyassociated with headache (13%), abdominal pain (4%) and nausea (4%). There were no changes in vital signs in either group. The results show that fluvoxamine has marked beneficial effects in preventing the recurrence of DSM-ill-R major depression and is safe during long-termadministration. References

Franchini, L., Gasperini, M.and Smeraldi, E. (1994) A 24-month follow-up study ofunipolar subjects: a comparison between lithium and ftuvoxamine. Journal of Affective Disorders 32,225-231. Martin, AJ. and Wakelin, J. (1986) Fluvoxamine - a baseline study of clinical response, long term tolerance andsafety in a general practice population. British Journal ofClinical Practice 40,95-99. Ottevanger, E.A. (l994) Long term treatment with ftuvoxamine in depression. Neuropsychopharmacology to (Suppl 3), 100S.

IP.1,017 1 Thecomparative effects of single andmultiple doses of R5-8359, moclobemlde andplacebo on psychomotor function in healthy subjects K. Puechler, K. Scheffler, C.-H. Wauschkuhn, A. Plenker. Sankyo Europe GmbH, Immermannstrasse 45, Dusseldorf40210, Germany

The psychophysiological/-motor effects of RS-8359 were evaluated in two, double-blind, double-dummy, cross-over studies. In the first, 10 healthy males (mean age 31 years, mean body weight 79 kg) received three differentsingledosesof RS-8359(50, 100or 300mg), moclobemide (150 mg)- as a reference- and placebo. In the second, 16 similarsubjects