Psychopharmacology (1992) 108:213-217

Psychopharmacology © Springer-Verlag 1992

Absence of withdrawal effects of ritanserin following chronic dosing in healthy volunteers F. KamalP, S.C. Stansfield 2, C.H. Ashton 1, G.L. Hammond 2, M.B. Emanuel 1, and M.D. Rawlins ~ 1 Department of Pharmacological Sciences, University of Newcastle upon Tyne, Tyne NE1 7RU, UK 2 Janssen Research Foundation, Janssen Pharmaceutical Ltd, Grove, Wantage, UK Received September 30, 1991 / Final version January 10, 1992

Abstract. The possible development of withdrawal symptoms following abrupt discontinuation of ritanserin after chronic administration of 10 mg daily for 8 weeks was investigated in a placebo controlled trial in 40 healthy subjects. The study consisted of two phases. In the first phase, under single blind conditions, all subjects received placebo for 2 weeks followed by a single daily dose of ritanserin (10 mg) for 8 weeks. In the second phase, under double blind conditions, subjects were randomised to receive either placebo or to continue on ritanserin (10 mg) for a further 4 weeks. Psychological assessments were performed at the start of and at intervals throughout the study. Levels of anxiety, concentration, quality of sleep and morning vigilance were measured throughout by daily visual analogue scales. No significant changes were detected in any of the measures in the group of subjects who received ritanserin compared to the group who received placebo during the second phase of the study. Ritanserin discontinuation following chronic dosing in healthy volunteers does not appear to be associated with withdrawal symptoms. Key words: Ritanserin - Anxiety - Sleep - Withdrawal effects

Most clinically effective anxiolytic and hypnotic drugs have the disadvantage of causing dependence and, in a significant proportion of patients, a withdrawal syndrome occurs on discontinuation. This property was characteristic of barbiturates and the early tranquiUiser meprobamate, and occurs with benzodiazepines (Kales et al. 1978; Petursson and Lader 1981; Owen and Tyrer 1983; Ashton 1984). Although benzodiazepines are highly effective and have a rapid onset of action, withdrawal effects can occur on cessation after only a few weeks of regular use (Murphy et al. 1984). Withdrawal effects are not confined to anxious patients but can also occur in Offprint requests to: F. Kamali

normal volunteers and in non-anxious patients administered benzodiazepines for sports injuries or as routine hypnotics in hospital (Lader 1988). An anxiolytic drug which was not associated with withdrawal symptoms would clearly offer a clinical advantage. The primary mechanism of action of benzodiazepines is enhancement of 7-aminobutyric acid (GABA) activity in the brain by an interaction with specific receptors on the GABAA receptor complex (Haefely 1990). The mechanism of the benzodiazepine withdrawal syndrome, which consists largely of anxiety, is not known but it may represent a state of GABA underreactivity (Nutt 1990) or an increase in the activity of endogenous benzodiazepine-like anxiogenic substances (File and Baldwin 1989). One of the effects of GABA enhancement by benzodiazepines is a secondary decrease in central serotonergic activity (Gray 1981), and recent interest has focussed on the role of serotonin in anxiety. There is evidence that anxiety is associated with increased activity of brain serotonergic systems and that drugs which decrease serotonergic activity have anxiolytic effects (Chopin and Briley 1987; Fozard 1987). Consequently, there has been a search for anxiolytic drugs which act specifically on serotonergic systems. Buspirone has partial agonist effects at serotonin (5-HT1A) receptors and probably decreases serotonin release and synthesis (Dourish et al. 1986). It has anxiolytic activity in man (Levine 1988) and is less likely than benzodiazepines to produce withdrawal effects (Tyrer et al. 1988). However, its onset of action may be delayed for 2 or 3 weeks (Murphy et al. 1988) and the drug is not efficacious in anxiety precipitated by benzodiazepine withdrawal (Lader and Olajide 1987; Ashton et al. 1990). Ritanserin is a serotonin 5-HTz and 5-HTlc receptor antagonist with no direct action at benzodiazepine receptors (Leysen et al. 1985; Hoyer 1988). It increases the duration of slow wave sleep in normal subjects, insomniacs, poor sleepers and dysthymics and improves subjective ratings of sleep quality in poor sleepers (Paiva et al. 1988; Adams and Oswald 1989; Ruiz-Primo et al. 1989;

214

Sharpley et al. 1990; Idzikowski et al. 1991). It also appears to have anxiolytic properties in animals and man (Meert 1986; Fozard 1987; Pangallila-Ratu-Langi 1988) although it was found not to be effective in panic disorder (Den Boer and Westenberg 1990). However, the potential of ritanserin to produce withdrawal effects after chronic administration has not been explored. In this preliminary investigation the effects of abrupt withdrawal of ritanserin were assessed in healthy volunteers. Materials and methods Subjects. Forty subjects (20 females) aged 18-39 years (median 20) agreed to take part in the study which was approved by the Newcastle Joint Ethics Committee. No subject had a history of alcohol or drug abuse, was taking any centrally acting medication (other than simple analgesics) during the 2 weeks preceding the trial, or had a history of psychiatric illness. None of the female subjects was breast feeding or pregnant, and all those sexually active were taking adequate contraceptive precautions. Subjects taking part in the study underwent a general medical examination and a 12 lead electrocardiogram on entry. Haematology, serum biochemistry and full liver function tests were performed at the start and at weeks 4, 8 and 12.

Procedure. During the first single-blind phase of the trial, all subjects received placebo for 2 weeks followed by a single daily therapeutic dose of ritanserin (10 mg) for 8 weeks. In the second doubleblind phase; the subjects were randomised into two equal groups of which one continued to take ritanserin at the same dose and the other received a matched placebo for a further 4 weeks. The study was designed in such a way that the randomisation to placebo or continued ritanserin was unknown to the subjects. In particular the change from fortnightly to weekly visits did not coincide with the start of the double-blind phase (Fig. 1). Assessments. Subject assessment and evaluation were carried out at entry and on 11 other occasions spaced at 1 or 2-week intervals as shown in Fig. 1. The assessments included the Spielberger Self Evaluation Questionnaire for trait-anxiety (STAI-II) and Eysenck Personality Questionnaire (EPQ) (Eysenck and Eysenck 1975) at entry only, and state-anxiety (STAI-I) and Hospital Anxiety and Depression Scale (HADS; Zigmond and Snaith 1983) throughout. Assessment of possible withdrawal symptoms was carried out using two methods. A list of 49 symptoms developed from previous studies of benzodiazepine withdrawal (Ashton 1984) were rated by subjects on a scale of severity (0 = none, 1 = mild, 2 = moderate and 3 = severe). Overall symptom scores were obtained from each visit.

Second, each day throughout the study, levels of daytime anxiety and concentration (just before going to bed), and quality of sleep and morning vigilance (within 30 min of getting out of bed) were assessed on 100 mm visual analogue scales. The boundaries of the scales were as follows: for anxiety: "imperturbable tranquillity" to "terrible agitation", for concentration: "wonderfully alert and penetrating mind" to "extremely difficult to concentrate", for sleep: "worst possible" to "best ever" and for morning vigilance: "marvellously alert and energetic" to "awfully sleepy and lack lustre". Adverse events, both physical and life events, were elicited by open questions. In addition, a record was kept of any prescription/nonprescription medication taken by each subject during the trial. Subject compliance was monitored by counting the number of tablets returned at each visit and by the measurement of ritanserin plasma concentrations (Larssen and Forsman 1987) at weeks 4, 8 and 12.

Analysis of data. Data were analysed using analysis ,of variance, comparing the treatment and period effects between the ritanserin and the placebo groups. For the VAS data, the area under the curve (AUC) was calculated for both groups of subjects for weeks 1-8 and weeks 9-12. The mean at week 8 was used as a covariate for the analysis of the data for weeks 9-12.

Results

Thirty-five subjects completed the study. Five dropped out either before or during the first 2-week (placebo period) of the trial for the following reasons: one male declined to participate before the start of the trial; one female subject (at week 2) thought that the medicine (placebo) was interfering with her studies; one female subject was withdrawn because she had a high-risk hobby incompatible with the study indemnity; and two female volunteers were recommended by their general practitioners to be withdrawn before the start of the trial. The baseline scores for STAI-II (36.0 + 6.6) and EPQ (psychotisism = 3.03, extraversion = 16.00, neurotisism = 9.54) were within the normal range for the subjects completing the study. There were no significant differences (Figs 2 and 3) in any of the psychological parameters (STAI-I, HADS) or symptoms scores (Fig. 4) between

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the two groups of volunteers who went on to receive either ritanserin or placebo during weeks 8-12. Likewise, the mean scores for the visual analogue scales for anxiety, concentration, morning vigilance and quality of sleep for the placebo and the ritanserin groups had similar profiles (Fig. 5). N o significant differences in A U C were found

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216 Table 1. Means4- SD (range) plasma ritanserin concentrations (ngmt-1) for weeks 4,8 and 12

Subjects receiving placebo weeks 8-12 Subjects receiving ritanserin weeks 8-12

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191.7+92.4 (77.9-449.0)

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discontinuation of ritanserin (10 mg daily) administered for 8 weeks to healthy young subjects. The elimination half-life of ritanserin is about 40 h (Van Peer et al. 1985) and any withdrawal symptoms should have appeared well within the 4 weeks of observation after drug cessation. Since visual analogue scores for anxiety, concentration, sleep quality and morning vigilance were completed daily any potential short-lived withdrawal effects, which may have occurred between weekly assessment visits, are unlikely to have been missed. The majority of the subjects had low scores for anxiety (with a median HAD rating at entry of 5 (range 1-16). Individual scores varied little throughout the study and were not altered either by administration of ritanserin for 8-12 weeks or by its withdrawal after 8 weeks. Similarly, subjective ratings of sleep quality were not influenced by ritanserin. This finding is in agreement with previous studies which showed that ritanserin (1-10 mg) increased the duration of slow wave sleep in young healthy volunteers but did not significantly affect subjective ratings of sleep quality (Idzikowski et al. 1987, 1991; Sharpley et al. 1990). Ritanserin has also been shown to increase the duration of slow wave sleep in middle-aged poor sleepers (Adam and Oswald 1989), insomniacs (Ruiz-Primo et al. 1989) and patients with dysthymic disorder (Paiva et al. 1988), without altering rapid eye movement sleep. In these subjects, ratings of sleep quality were improved. In a single-blind study of middle-aged poor sleepers, sleep impairment (decreased total sleep duration and worsening of subjective ratings of sleep quality) was claimed on withdrawal of 5 mg of ritanserin following 20 days' treatment (Adam and Oswald 1989), but no such decline was reported in volunteers participating in the present investigation. In conclusion, no withdrawal effects were detected following abrupt discontinuation of ritanserin after chronic administration to healthy volunteers. This finding contrasts with observations in volunteers receiving benzodiazepines (Allen and Oswald 1976) or barbiturates (Ogunremi et al. 1973), in whom discontinuation of 4-5 weeks' treatment precipitated withdrawal symptoms. We therefore anticipate that withdrawal problems following ritanserin treatment in anxious patients may be less likely.

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