THE EFFECTS OF RITANSERIN ON MOOD, SLEEP, VIGILANCE, CLINICAL IMPRESSION, AND SOCIAL FUNCTIONING IN ALCOHOL-DEPENDENT INDIVIDUALS

G. A. Wiesbeck*, H.-G. Weijers, J. Chick1, J. Boening and on behalf of The Ritanserin in Alcoholism Work Group2

Alcohol Research Program, Psychiatric Clinic, University of Wuerzburg, Germany and
1 Alcohol Problems Clinic, 35 Morningside Park, Edinburgh, UK

Received 7 January 1999; in revised form 1 March 2000; accepted 28 March 2000


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
In an international double-blind placebo-controlled trial with 493 detoxified alcohol-dependent individuals, ritanserin, a specific 5-hydroxytryptamine2 antagonist, was tested in three different dosages (2.5, 5, and 10 mg/day) against placebo over a period of 6 months. Data on changes in mood state, sleep quality, morning vigilance, clinical impression, and social functioning were analysed. None of the three dosages of ritanserin given revealed any significant effect against placebo on the above-mentioned parameters either at the end of treatment or upon relapse. Therefore, we conclude that patients suffering from alcohol dependence without concomitant psychiatric disorders do not benefit from additional treatment with (2.5, 5, or 10 mg/day) ritanserin.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Ritanserin is known to bind selectively to 5-hydroxytryptamine2 (5-HT2) receptor sites with high affinity both in vitro and in vivo (Leysen et al., 1985Go; Van Nueten et al., 1986Go). Additionally, the substance revealed a high potency in several tests related to 5-HT2 antagonism (Awouters et al., 1988Go). Since serotonergic transmission seems to play an important role in the biology of alcohol misuse and dependence (Sellers et al., 1992Go; LeMarquand et al., 1994Go; Boening, 1996Go), this binding profile attracted the attention of several groups working in alcohol research (Meert et al., 1991Go; Monti and Alterwain, 1991Go; Rammsayer and Vogel, 1991Go; Monti et al., 1993Go; Estevez et al., 1995Go; Naranjo et al., 1995Go; Johnson et al., 1996Go).

In an international double-blind placebo-controlled trial with 493 detoxified alcohol-dependent individuals, ritanserin in three different dosages (2.5, 5, or 10 mg/day) was not able to significantly improve the alcoholics' probability of remaining abstinent (Wiesbeck et al., 1999Go). However, ritanserin is well known for its positive effects on mood, quality of sleep, morning vigilance, and daytime functioning. For example, ritanserin produced a sleep-improving effect and a faster transition from waking to sleep in animals (Kirov and Moyanova, 1995Go, 1998Go; Moyanova et al., 1998Go). It increased total time spent in deep sleep and sleep episode length in rats (Detari et al., 1999Go). In humans, it increased slow wave sleep (stages 3 and 4) as well as quality of sleep in healthy volunteers, whereas morning vigilance remained unimpaired (Idzikowski et al., 1986; Declerck et al., 1987Go). Ritanserin improved negative mood states, insomnia and daytime functioning in dysthymic patients and in patients suffering from depression (Arriaga et al., 1986Go; Hoppenbrouwers et al., 1986Go; Reyntjens et al., 1986Go; Strauss and Klieser, 1991Go; Bakish et al., 1993Go).

In an open study with five male alcoholics, taking ritanserin was associated with improvement in the subjects' condition as measured by the Clinical Global Impression (CGI) instrument, and with a significant decrease in the mean score on the Hamilton Depression Rating Scale (HDRS) (Monti and Alterwain, 1991Go). Alcohol-dependent subjects with a personality disorder suffering from dysthymia responded with a decrease in depression scores and with sleep improvement to ritanserin administration (Monti et al., 1993Go). Nevertheless, experiences with the psychotropic effects of this medication in alcohol-dependent individuals are rare.

Though failing in relapse prevention (Wiesbeck et al., 1999Go), we wondered if ritanserin might be useful as a pharmacological adjuvant in alcohol dependence by improving mood, sleep, vigilance, clinician's global impression, and social functioning — parameters known to be affected in alcoholic individuals even with no clinically relevant psychiatric diagnosis other than alcohol dependence. We hypothesized that ritanserin would be more highly associated, than placebo, with improvement in the above parameters.


    PATIENTS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
This study was conducted in accordance with the current version of the Declaration of Helsinki and with the full approval of the Ethics Committees of each of the 54 centres participating. The data presented here are derived from a double-blind placebo-controlled multicentre study on the effectiveness of ritanserin in relapse prevention in detoxified subjects suffering from moderate or severe DSM-III-R alcohol dependence (American Psychiatric Association, 1987Go).

After informed consent, 493 alcoholics, both women and men, were randomly assigned to either one of four treatment groups (2.5, 5, 10 mg/day ritanserin, or placebo). At that time, patients were completely abstinent from alcohol, at 2–6 weeks after detoxification and without symptoms of withdrawal. Any of the following criteria led to exclusion: psychoactive substance abuse/dependence (except alcohol and nicotine), concomitant axis-I or axis-II psychiatric disorders, severe organic disorders, or (possible) pregnancy.

Patients received one tablet (2.5, 5, 10 mg/day ritanserin or placebo) once daily in the morning with breakfast for a period of 24 weeks. The tablets were identical in appearance and size. Blood samples controlling for ritanserin concentrations as well as liver enzymes and alcohol levels were drawn regularly throughout the 6-month trial. The following parameters were assessed: mood state, HDRS (Hamilton, 1960Go); sleep quality and morning vigilance, questions; clinical observer's impression, CGI (Guy, 1976Go); social functioning, Social Functioning Questionnaire (SFQ; Tyrer, 1990Go). Patients were rated at regular screening visits weekly during the first month, 2-weekly during months 2–3, and monthly during months 4–6.

The analysis of the above-mentioned parameters focused on three different periods: first, ‘before detoxification’ in order to describe the situation before ritanserin/placebo treatment was initiated; second, ‘at end point’ which means the last evaluation available for each individual. The difference in numbers between ‘before detoxification’ (n = 493) and ‘at end point’ (n = 473) is due to early drop-outs after randomization. Finally, we focused on those patients who returned to alcohol consumption (n = 179) with a third time of analysis taking place ‘at relapse’ (‘relapse’ was diagnosed in three different ways: ‘physiological relapse’ based on elevation of liver function test parameters, ‘self-reported relapse’ based on the patients' self-reports on quantity and frequency of drinking, and relapse based on the investigator's clinical impression).

To detect differences between the four treatment groups, the Cochran–Mantel–Haenszel (CMH) test was performed; all test results were interpreted at the 5% significance level (two-tailed).


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Table 1Go demonstrates that the four groups were comparable in the main features characterizing alcohol drinking behaviour. Drop-out rates were high for each group, including the placebo-treated subjects. A survival analysis found no statistically significant superiority of any ritanserin dosage against placebo in preventing relapse. This result has been reported and discussed in more detail elsewhere (Wiesbeck et al., 1999Go).


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Table 1. Characteristics of the four treatment groups
 
Figure 1Go demonstrates the effect of ritanserin on mood states as reflected by the HDRS. Total scores are given as means for each treatment group at the three different times: before detoxification, at the end point (e.g. the last available evaluation), and at the time when relapse occurred (as defined above). The four groups were comparable at the starting point (CMH test on four treatment groups before detoxification: P = 0.339). As expected, all scores were in the low range, since a HDRS total score <=18 was required as inclusion criterion. The bars suggest a slight tendency towards higher HDRS scores over the trial period for both ritanserin and placebo. ‘Highest’ scores were reached when relapse occurred, but even then, none of the four groups revealed a mean score higher than 7 (possible range: 0–52) indicating that depression did not occur in any group.



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Fig. 1. The effect of ritanserin on mood state.

 
Ritanserin-treated patients did not differ from placebo-treated patients. Comparing each ritanserin group against placebo ‘at end point’ revealed no statistically significant differences (2.5 mg ritanserin vs placebo: P = 0.595; 5 mg ritanserin vs placebo: P = 0.176; 10 mg ritanserin vs placebo: P = 0.148). At the time when subjects relapsed, between-group differences did not reach statistical significance either (2.5 mg ritanserin vs placebo: P = 0.455; 5 mg ritanserin vs placebo: P = 0.296; 10 mg ritanserin vs placebo: P = 0.744). Taken together (2.5, 5, or 10 mg), ritanserin medication yielded no significant effect on mood states in non-depressed alcoholics — neither at the time of relapse nor at the end of continuous treatment.

Sleep quality and morning vigilance were self-rated, each scoring from 0 to 3 (the lower, the better). Figure 2Go demonstrates that there was no insufficiency in sleep quality at the first rating when subjects were still under the influence of alcohol. Before detoxification mean scores ranged between 0.95 (placebo) and 1.15 (10 mg ritanserin) reflecting an altogether ‘good’ (= 1) quality of sleep for each treatment group. The CMH test on four treatment groups yielded no significant differences ‘before detoxification’ (P = 0.347).



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Fig. 2. The effect of ritanserin on sleep quality.

 
This situation did not change significantly at ‘the end point’ nor when relapse occurred (Fig. 2Go). At both times, mean scores for sleep quality still ranged closely around 1 for each group, indicating that subjects assessed their quality of sleep far more as ‘good’, than as ‘moderate’. There was no difference between ritanserin- and placebo-treated patients. Between-treatment-group differences did not reach statistical significance — either at ‘the end point’ or at the time when subjects relapsed.

While the four groups were similar in HDRS and sleep quality scores before detoxification, they were not comparable in their level of morning vigilance at that time (Fig. 3Go). Subjects in the 2.5-mg ritanserin group rated their vigilance significantly worse than subjects in the placebo group [1.1 (± 0.081) vs 0.89 (± 0.081); P = 0.039]. However, this lack of vigilance disappeared at further assessments, and no significant differences could be found — either at the end of continuous treatment or at relapse.



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Fig. 3. The effect of ritanserin on morning vigilance.

 
At each visit, the investigator scored their CGI of the patient. Figure 4Go demonstrates the mean scores across the four groups before detoxification, at the end, and at the time of relapse. Statistical evaluation of between-treatment-group differences yielded no significant superiority of (2.5, 5, or 10 mg) ritanserin against placebo at any of these three time points.



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Fig. 4. The effect of ritanserin on global clinical impression.

 
Social functioning scores ranged from 0 to 24, with the lower the score, the better the functioning. Before detoxification, subjects in the 10-mg ritanserin group happened to score significantly worse in social functioning than subjects in the placebo group P = 0.048; Fig. 5Go). At the end of treatment, this difference was still recognizable; however, it did not reach statistical difference (10 mg ritanserin vs placebo: P = 0.071). Interestingly, at that time, subjects receiving placebo (SFQ score: 5.72 ± 0.44) reached significantly better social functioning scores than subjects treated with 2.5 mg ritanserin (SFQ score: 7.09 ± 0.51; CMH test on 2.5 mg ritanserin vs placebo: P = 0.042). Between-treatment-group differences in social functioning did not reach significance, however, when subjects relapsed.



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Fig. 5. The effect of ritanserin on social functioning.

 

    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
It is well documented that ritanserin has positive effects on mood, sleep, vigilance, and daytime functioning in some patients (Idzikowski et al., 1986; Reyntjens et al., 1986Go; Declerck et al., 1987Go). There are reports that this medication is well-tolerated and that particularly individuals suffering from dysthymia may benefit from its use (Arriaga et al., 1986Go; Hoppenbrouwers et al., 1986Go; Bakish et al., 1993Go). However, there are only a few clinical reports in the literature dealing with the effects of ritanserin in alcohol consumers (Monti and Alterwain, 1991Go; Ansoms et al., unpublished data; Monti et al., 1993Go; Naranjo et al., 1995Go). Only one of these (Monti and Alterwain, 1991Go) focused on alcohol-dependent subjects (n = 5) while the others treated excessive drinkers not necessarily meeting criteria for dependence, or alcoholic subjects with an additional personality disorder (Monti et al., 1993Go). To the best of our knowledge, this is the first report investigating the psychotropic effects of ritanserin on mood, sleep, vigilance, clinical impression, and social functioning in individuals meeting criteria for no psychiatric diagnosis other than alcohol dependence.

This paper focused on different times within the 6-month duration of treatment. First, we asked whether alcohol-dependent subjects taking ritanserin improved more than patients taking placebo at the end (e.g. last evaluation available), and second, whether there was an effect of ritanserin in relapsed patients at the time of relapse. Taken together, the results were negative. None of the three different dosages of ritanserin given revealed any significant advantage over placebo on the parameters investigated either ‘at the end point’ or ‘at relapse’. Furthermore, at the end, placebo-treated patients did significantly better in social functioning than 2.5-mg ritanserin-treated ones. This discouraging result, however, has to be viewed in the light of the absolute SFQ scores. Both groups scored in the lower range, meaning that, though significantly different, both groups were a long way from ‘bad’ social functioning.

The subgroup of patients tested at relapse showed slightly higher HDRS scores than patients ‘before detoxification’ or ‘at the end point’. There are three interpretations conceivable. First, the increase in HDRS scores in both ritanserin- and placebo-treated subjects might have occurred as a reaction to the relapse itself (‘having failed’). Second, a decrease in mood levels could also have been a reason for relapsing. Third, we have not examined whether those who relapsed were those who had a higher score at entry to the study. Either way, none of the three dosages of ritanserin showed any significant superiority against placebo in relapsed patients. Though there was a slight increase in HDRS scores at relapse, the mean scores below 7 for all four groups ‘at relapse’ do not justify a diagnosis of depressed mood.

The negative results of this study have also to be seen in the light of the methods used. First, this was not a study on depressed alcoholics. Furthermore, mood and sleep changes in alcoholics may be viewed differently than those experienced by depressed patients. Therefore, existing experiences with ritanserin in dysthymic subjects seem to be of limited comparability with the experiences of this trial.

The subjects participating did not suffer from clinically relevant disorders of sleep or vigilance, or from poor social functioning, since it was not the intention of this trial to test ritanserin in medicating for these disorders when meeting severity of a concomitant axis-I or axis-II diagnosis. The intention was to investigate the potential effects of ritanserin in otherwise undisturbed alcoholics during their first months of abstinence. Therefore, the data presented do not allow an overall conclusion regarding the usefulness of ritanserin in clinically relevant depression, sleep disorders or severely disturbed social functioning.

Thus, in conclusion, although this was a study on subjects meeting only criteria for alcohol dependence, this is still a relevant group of alcoholics admitted to psychiatric hospitals (Wiesbeck et al., 1994Go). According to the data presented, such patients do not benefit in their mood, sleep, vigilance, or social functioning from an additional treatment with ritanserin during their first months of abstinence.


    ACKNOWLEDGEMENTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
This study was supported by the Janssen Research Foundation.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
* Author to whom Correspondence should be addressed at: Alcohol Research Program, Department of Psychiatry, University of Wuerzburg, Fuechsleinstr. 15, 97080 Wuerzburg, Germany. Back

2 Participating countries and investigators: Australia: Bell, J., Cuningham, E., Keirnan, M., Kronborg, I. J., Price, J., Sunders, J., Stanhope, J.; Austria: Saletu, M.; Belgium: Ansoms, C., De Brave, C., Degroote, W., De Winter, A., Hebbrecht, M., Motte, D., Pelc, J., Santens, P., Vacher, C., Van de Velde, I., Van Moffaert, M.; Canada: Naranjo, C.; France: Archambault, J. C., Beauvalot, Y., Boisset, B., Claudot, E., Clervoy, P., Didi, R., Favre, J. D., Guibe, P., Lassagne, M., Maire, N., Payen, A., Reocreux, M., Toulose, A.; Germany: Boening, J., Hippius, M., Klingler, T., Lamberty, H., Leipnitz, B., Mauerer, C., Steinkirchner, R., Thome, J., Wodarz, N., Wiesbeck, G. A.; Great Britain: Chick, J., Goldbeck, R., Jauhar, P., Luthra, J., Mitchell, C., Sowerbutts, K.; South Africa: Miranda, S., Osler, B., Schaefer, C.; Sweden: Bjork, K., Grishammar, R., Gabrielsson, E., Gyllenhammar, C., Reed, C., Malm, K., Nilsson, L., Sternebring, B. Back


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 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
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