The comparative effects of single and multiple doses of RS-8359, moclobemide and placebo on psychomotor function in healthy subjects

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

P.1 Affective disorders and antidepressants

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each received daily doses of RS-8359 (100 or 300 mg), moclobemide (300 mg) or placebodivided b.i.d. for one week. Effects on psychophysiological/-motor function wereevaluated in each studyafter the last dose by: 1. Auditory Evoked Potentials (AEP): amplitude and latencies of the first two evoked potential components Nl and P2 from Vertex EEG - checking the afferent CNS information processing and CNS-drug bioavailability. 2. The Oculodynamic Test(ODT): consisting of the electro-oculogram (EOG) - measuring latency and fixation times, angular velocity of saccadiceyemovements; a complexchoice-reaction task(CRT) reaction time and numberof correctresponses, as wellas cardio-respiratory parameters underworkload - checkingafferent and efferent CNS processing. 3. VisualAnalogue Scales (VAS) for the following items: excitation, dizziness, tremor, nausea, vertigo, ODT performance, ODT effort, dry mouth, restlessness - assessing the subjective impressions of well-being and drug effects. Results; In the single dose study, 300 mg RS-8359 in comparison with placebo showed a significant (p < 0.05) increase in AEP NI and P2 amplitude, a significant (p < 0.05) decrease in NI and P2 latency in comparison with placebo. Although not significant, the number of correctresponses in the CRTpart of ODTwas increased and the reaction time was decreased for the 300 mg RS-8359 preparation compared with placebo. The visual analogue scales (VAS) showed a significant increase in tremor, nausea and vertigo with 300 mg RS-8359, and a marked decrease in wakefulness for the 100mg and 300 mg dosageof RS-8359. In the multiple dose study, there were no significant effects on any of the AEP variables although the ranking of N1 latencies was consistent on each assessment day up to 9 hours after dosing. The P2 amplitudes of AEP were increased after all active medications. with 150 mg b.i.d. RS-8359 demonstrating the most pronounced effect. The 150 mg b.i.d, RS 8359 dosage also showed a significant decrease in EOG latency compared with the 50 mg b.i.d. dosageof RS 8359. All active drugswere rated lower than placebo in the VAS wakefulness item. This effect was most pronounced with 150mg RS-8359 and 150mg moclobemide. Conclusions: The results from both studies suggest that RS-8359 demonstrates a definite CNS-bioavailability and enhances psychophysiological as well as psychomotor functions compared to placebo. Similar effects are seenfor moclobemide in someof the tests.

IP.1.018! The safety and tolerability profile of a new RIMA

antidepressant, R5-8359 in healthy subjects and depressed patients

K. Puechler, A. Plenker, H.-P. Volz, P.U. Witte. Sankyo Europe Gmbll,

lmmermannstrasse 45, Dusseldorf402I0, Germany The safety and tolerability profile of RS-8359 has been evaluated in a total of 235 healthysubjects(16 elderly, 219 adults) usingdaily doses up to 400 mg as singledoses, and repeated dosesup to 200 mg b.i.dfor four weeks and 100 mg b.i.d for six weeks. To date. 550 depressed patients have been randomised to three Phase IT clinical trials. They have been treated with dosages from 25 mg b.i.d. RS 8359 up to 100 mg b.i.d, RS 8359 for a duration up to 6 weeks. About half of these patients were in-patients. Results; The most frequently occurring adverse events (c- 5%) in healthy subjects were diarrhoea, headache, nausea. vomiting, stomach upset, and tiredness. These were usually of mild to moderate severity and most frequent during the first one to two weeks of treatment, The incidence of headache, nausea and vomiting showeda higher incidence with increasing dosesof RS-8359. In the comparison of adultand elderly subjects, the most frequent events in both groups were headache, nausea and vomiting. A tendency toward increases in serum creatinine was seen in subjects treated with 200 mg RS-8359 for four weeks, although no clinically significant increases were observed. There were no clinically relevant changesinotherlaboratory variables or vitalsigns, and no serious adverse events. To date, 550 depressed patients. about half of whom are in-patients, havebeenrecruited to PhaseIT clinicaltrials. Themostfrequently reported adverse eventsare anxiety, headache, gastric upset and tachycardia. The

majority of events are of mild to moderate severity and OCCUlTed early in treatment, To date, therehavebeen no clinically relevant changesin vital signsor laboratory parameters. Fifteen serious adverse events havebeen reportedin depressed patients including three attempted suicides, one case of acute cholelithiasis, and one patient with an acute confusional state when lithium was taken in addition to study medication. All the patientsrecovered withoutsequelae and noneof the events was considered to be relatedto study medication. Conclusions: Overall, RS-8359 is apparently safe and well tolerated in doses up to 400 mg daily although some minor adverse events showeda dose-related incidence. The adverseevent profiles are similar in healthy subjects and depressed patients. Changes in laboratory parameters and vital signs were also similar in the two populations, and were not considered to be clinically relevant or drug related.

IP.1.019! Theeffects of a newRIMA antidepressant R5-8359 on cardiovascular function

K. Puechler, A. Plenker, H.-P. Volz, P.U. Witte. Sankyo Europe Gmbll, lmmermannstrasse 45, Dusseldorf40210, Germany To date 13 clinical trials have been performed. About 800 healthy volunteers and depressed patients have been treated with RS 8395. Daily doses up to 400 mg as single dose and repeated doses up to 200 mg b.i.d. for four weeks and 100 rng b.i.d. for six weeks were used. In all studies cardiovascular parameters have been evaluated: ECG. pulse rate, blood pressure and cardiovascular related adverse events. In one trial the possible interaction of repeated doses of RS 8359 with tyramine, the 'cheese effect' has been determined. This study (n = 24), was a double-blind, three group, three period, randomised, crossoverstudy of repeated dosesof RS 8359(200 mg b.i.d.),moclobemide (300 mg b.i.d.), or placebo in healthy subjects. Results; In healthy subjects (n = 235), and in depressed patients (n = 550) no serious adverse events have been observed in cardiovascular function. No clinically relevant changes in ECG, pulse rate, systolic or diastolic bloodpressureoccurred in healthysubjects using daily doses up to 400 mg as singledose, and repeated doses up to 200 mg b.i.d,for four weeksand 100mg b.i.d. for six weeks.Also, in depressed patientstreated with dosages from 25 mg b.i.d, up to 100 mg b.i.d, for a duration of up to six weeks, no clinically relevant findings regarding cardiovascular function wereobserved. Almostall volunteers in the repeated dosingstudyshowedthe tyramine dose necessary to raise the systolic blood pressure (SBP) 30 mmHg above baseline was smaller following RS-8359 and moclobemide than following placebo. The arithmetic means of PDJO for RS-8359 and moclobemide weresimilar(4.5 mg and4.18 mg, respectively) and both were significantly (p < 0.05)lowerthanplacebo(10.84mg). The average PDJO ratio of moclobemide to RS-8359 at steady state is 0.98 (± 0.42). The maximum SBP rise was higher, and the time to reach this level longer, withbothactive drugsthan withplacebo. Noneof the volunteers required any rescue medication duringor after the tyramine pressor test. Conclusion; There has been no evidence from studieseither in healthy subjects or depressed patients of clinically relevant changesin vital signs related to cardiovascular function. The PDJO ratiosseenwith dosesof 200 mg b.i.d of RS-8359 are comparable with other reversible and selective monoamine oxidase A inhibitors. Therefore, RS-8359 is considered safe withrespect to cardiovascular function and tyramine interaction.

IP.1.020 I ofSerotonergic mechanisms In the pathophysiology seasonal affective disorder A. Neumeister I, N. Praschak-Rieder 1, B. Hesselmann I, M. Rauh 2, A. Barocka 3, O. Vitouch " S. Kasper '. 'Department of General Psychiatry, Vienna University. Wtihringer GuneI18-20. 1090 Vienna, Austria; 1 Department of Pediatry; University of Erlangen, Loschgestrasse /5. 91054Erlangen, Germany; 3 Department of Psychiatry, University of Erlangen; Schwabachanlage 6. 91054 Erlangen, Germany Seasonal affective disorder/winter type (SAD) is characterized by the annual reoccurrence of depressive episodes during fall and winter with