Oxytocin inhibits hindpaw hyperalgesia induced by orofacial inflammation combined with stress.

Oxytocin (OT) is recognized as a critical neuropeptide in pain-related disorders. Chronic pain caused by the comorbidity of temporomandibular disorder (TMD) and fibromyalgia syndrome (FMS) is common, but whether OT plays an analgesic role in the comorbidity of TMD and FMS is unknown. Female rats with masseter muscle inflammation combined with 3-day forced swim (FS) stress developed somatic hypersensitivity, which modeled the comorbidity of TMD and FMS. Using this model, the effects of spinal OT administration on mechanical allodynia and thermal hyperalgesia in hindpaws were examined. Furthermore, the protein levels of OT receptors and 5-HT2A receptors in the L4-L5 spinal dorsal horn were analyzed by Western blot. The OT receptor antagonist atosiban and 5-HT2A receptor antagonist ritanserin were intrathecally injected prior to OT injection in the separate groups. Intrathecal injection of 0.125 µg and 0.5 µg OT attenuated the hindpaw hyperalgesia. The expression of OT receptors and 5-HT2A receptors in the L4-L5 spinal dorsal horn significantly increased following intrathecal injection of 0.5 µg OT. Intrathecal administration of either the OT receptor antagonist atosiban or 5-HT2A receptor antagonist ritanserin blocked the analgesic effect of OT. These results suggest that OT may inhibit hindpaw hyperalgesia evoked by orofacial inflammation combined with stress through OT receptors and/or 5-HT2A receptors, thus providing a therapeutic prospect for drugs targeting the OT system and for patients with comorbidity of TMD and FMS.

Effect of the serotonin antagonists ritanserin and ketanserin in Cushing's disease.

Central serotonergic regulation could have a role in the course of pituitary-dependent Cushing's disease. We studied the effects of ritanserin and ketanserin, two related selective 5HT2 receptor antagonists, in 11 patients with Cushing's disease. Treatment lasted from 1 month to 1 year (up to 4 years in one patient). Daily doses were 10-15 mg for ritanserin, and 40-80 mg for ketanserin. Since the two drugs share the same mechanism of action and no qualitative or quantitative differences in response to their administration were observed, the results were pooled together. Patients were assessed by clinical and hormonal evaluation. Urinary cortisol and ACTH were considered the parameters of interest. Short-term response: after 1 month, there was a significant decrease of urinary cortisol from 781 (160) to 331 (215) nmol/d (P < 0.02) while ACTH was 9.8 (1.5) pmol/L baseline and again 8.8 (2.2) pmol/L at 1 month (P = NS). For 9 patients, hormonal parameters were available after 1 week of treatment. In this case, also ACTH levels were significantly decreased (from 9.6 (1.7) to 5.2 (1.3) pmol/L; P < 0.01) together with urinary cortisol (from 781 (194) to 372 (165) nmol/d; P < 0.01). Long-term response: in 3 patients, hormonal parameters failed to respond to serotonin receptor antagonists, which were thus discontinued. An improvement was recorded in the remaining 8 patients, that was prolonged in 3, and transient in 5. In 3 of these latter patients, a marked increase of ACTH was observed before treatment discontinuation. Ketanserin was given to 2 patients with Nelson's syndrome, with only transient ACTH decrease in one, and no changes in ACTH response to CRH after 1 month treatment in both cases. An inhibitory effect of ritanserin and ketanserin on ACTH and cortisol production in Cushing's disease appeared to be limited both in terms of duration of response and number of patients with a satisfactory outcome. However, the results may provide a better understanding of serotonergic modulation in Cushing's disease and lead to therapeutic developments.

Ritanserin in relapse prevention in abstinent alcoholics: results from a placebo-controlled double-blind international multicenter trial. Ritanserin in Alcoholism Work Group.

Ritanserin, a long-acting specific 5-HT2 receptor antagonist, revealed promising effects on alcohol intake behavior in both animal and preliminary human studies. To test its effectiveness in alcohol dependence this phase III clinical trial was initiated. In a placebo-controlled, randomized, double-blind international multicenter study 493 patients with moderate or severe alcohol dependence (DSM-III-R) were treated with three doses of ritanserin 2.5 mg/day (n = 122), 5 mg/day (n = 123), 10 mg/day (n = 126), or placebo (n = 122) over a period of 6 months. Ritanserin was well tolerated. The most frequent adverse experiences were headache and insomnia. A small increase in weight in the ritanserin-treated patients was observed. There were no significant differences between any dose of ritanserin and placebo in the relapse-rate, the time to relapse, craving for alcohol, or quantity and frequency of drinking after relapse. So far, neither ritanserin nor any other serotonergic medication has shown its specific effectiveness in relapse prevention in alcohol dependence.

Ritanserin facilitates anxiety in a simulated public-speaking paradigm.

The effects of ritanserin, a 5-HT2A/2C (5-hydroxytryptamine) antagonist, have been investigated in simulated public speaking with healthy volunteers. The aim was to investigate the role of 5-HT in subjective experimental anxiety. There were three experimental groups each comprising four or five males and 11 females. Subjects received placebo, ritanserin 2.5 or 10 mg, p.o. They rated themselves using the Spielberger State-Trait Anxiety Inventory and visual analogue scales factored into anxiety, sedation and discontentment scores. Autonomic measures included skin conductance and heart rate. Subjects were told, 75 min after drug or placebo ingestion, without prior warning, to prepare a 4-min speech. Measures were taken before, during and after the speech. Ritanserin prolonged the anxiety induced by the procedure on the subjective ratings but had minimal effect on autonomic responses to the procedure. The result contrasts with an anxiolytic-like effect of ritanserin on aversively conditioned autonomic responses. The present finding is compatible with animal behavioural evidence that 5-HT has distinct and opposing roles in modulating conditioned and unconditioned anxiety.

Ritanserin in the treatment of alcohol dependence--a multi-center clinical trial. Ritanserin Study Group.

Four hundred and twenty-three alcohol dependent subjects were enrolled into a 12-week randomized, double-blind, placebo-controlled study to determine the safety and efficacy of the 5-HT2 receptor antagonist, ritanserin (2.5 mg/day or 5 mg/day), in reducing alcohol intake and craving. All subjects received 1 week of single-blind placebo prior to randomization into the 11-week double-blind phase. Additionally, all subjects received weekly individual sessions of manual-guided cognitive-behavioral therapy. Comparing the single-blind period with endpoint, there was approximately a 23% reduction in drinks/day; 34% fall in the total number of drinking days/week; 22% decrease in drinks/drinking day; and a 37% diminution in alcohol craving for all treatment groups. All treatment groups experienced a beneficial clinical outcome as assessed by the Clinical Global Impression Scale. There was, however, no significant difference between treatment groups on any of these measures of alcohol drinking, craving, or clinical outcome. Subjects were of relatively high social functioning at baseline, and this did not change significantly during treatment. Treatment groups did not differ significantly on either medication compliance or reported adverse events. Ritanserin treatment was associated with a dose-related prolongation of subjects' QTc interval recording on the electrocardiogram. These results suggest that alcohol dependent subjects can show marked clinical improvement within a structured alcohol treatment program. These findings do not support an important role for ritanserin in the treatment of alcohol dependence.

Failure of ritanserin to block cocaine cue reactivity in humans.

As part of a double-blind placebo-controlled study of the effects of ritanserin on cocaine use and craving, reactivity to cocaine-related events was assessed both before and during medication. Twenty-two patients receiving ritanserin and 23 receiving placebo were exposed to cocaine cues while continuous measures of heart rate, skin temperature, and skin resistance were taken. Self-reports of high, withdrawal, and craving were also collected. The cues produced significant physiological responding as well as significant increases in high and craving during both sessions. Ritanserin reduced cue-elicited decreases in skin temperature, but had no effect on heart rate and skin resistance or on cue-induced high and craving. The results demonstrate that cue reactivity is a robust phenomenon across two assessment sessions but fail to support the use of ritanserin as a means of reducing cue-elicited drug states.

Serotonin-2 and dopamine-1 binding components of clozapine in frontal cortex and striatum in the human brain visualized by positron emission tomography.

The specific binding of N-methyl-11C-clozapine in the human brain was studied in five healthy volunteers with positron emission tomography (PET). Four of the volunteers were reexamined after treatment with the dopamine D1 and D2 receptor antagonist flupenthixol, and all five volunteers were reexamined after pretreatment with the serotonin2 receptor antagonist ritanserin. The examinations after flupenthixol and ritanserin treatment were performed on different occasions. In the flupenthixol part of the study, two of the subjects were given an oral dose of 1 mg flupenthixol 2-3 h before the posttreatment study with PET. The other two subjects received 0.5 mg orally three times during the 24 h preceding the posttreatment PET study, with the last dose being administered < or = 4 h before the scan. All five ritanserin-treated subjects followed the same dosing regimen. During the 5 days preceding the posttreatment PET study, they were given a 10-mg tablet of ritanserin in the evening. The last dose was administered 2-1/2 hours before the study. Both flupenthixol and ritanserin pretreatment were associated with decreased binding of N-methyl-11C-clozapine in dorsolateral and medial frontal cortical regions. These results support previous findings that clozapine has affinity for both dopamine D1 and serotonin 5-HT2 receptors in the human frontal cortex. No consistent change of binding was observed in striatal regions following flupenthixol or ritanserin pretreatment. The clinical aspects of this feature are discussed, both with respect to efficacy and side effects.

Ritanserin, a central 5-HT2 antagonist, in heavy social drinkers: desire to drink, alcohol intake and related effects.

Ritanserin, a 5-HT2 receptor antagonist, decreased alcohol intake in some, but not all, animal studies and in an open clinical study. We tested the short-term effects of ritanserin in 39 (35 male, four female) heavy social drinkers (consuming at least 28 drinks/week), aged 19-63 years, who were not seeking treatment. After an intake assessment, they received placebo for 7 days in a single-blind baseline. They were then randomly assigned to one of three double-blind treatments for 14 days: ritanserin 5 mg/day (n = 12), ritanserin 10 mg/day (n = 13) or placebo (n = 14). Subjects recorded daily outpatient alcohol intake. Feelings of intoxication and interest, desire, craving and liking for alcohol were rated retrospectively at each weekly study visit. Experimental drinking sessions were conducted after baseline (EDS1) and treatment (EDS2); in each session subjects were offered 18 mini-drinks (total = six standard) and rated their desire to drink, intoxication and mood (POMS). Outpatient results: ritanserin 5 mg/day decreased desire and craving for alcohol (vs. baseline, p < 0.05) but not alcohol intake. Liking of alcohol decreased from baseline with ritanserin 10 mg/day (p = 0.01) and placebo (p = 0.05). Changes in alcohol intake from baseline with ritanserin 10 mg/day (increase, p > 0.05) and placebo (decrease, p > 0.05) were different (p < 0.05). EDS results: in EDS2, desire ratings for the first three mini-drinks were lower after ritanserin 5 mg/day than after ritanserin 10 mg/day (p < 0.05), but the decreases were not statistically significant when EDS1 desire ratings were controlled for. Ritanserin 10 mg/day increased alcohol-induced feelings of intoxication and friendliness, compared with placebo (p < 0.05). Both ritanserin 5 mg/day and 10 mg/day enhanced alcohol-induced decreases in fatigue, compared with placebo (p < 0.05). These results indicate that ritanserin may have differential effects on alcohol intake, desire, craving and liking, intoxication and some of alcohol's effects on mood. However, they suggest that ritanserin has limited efficacy in reducing alcohol intake in heavy drinkers.

An open clinical and biochemical study of ritanserin in acute patients with schizophrenia.

The effect of the selective serotonin-2 antagonist ritanserin was investigated in an open study of patients with schizophrenia. The patients were in an acute psychotic state considered to require neuroleptic medication. No neuroleptic drug was allowed during the study or during the last month preceeding the study. Oxazepam or nitrazepam were allowed for sedation or sleep inducement. Safety, tolerability, potential antipsychotic effect, and drug effects on monoamine metabolites in serum and CSF and prolactin in serum were evaluated. Central D2-dopamine receptor occupancy was determined by positron emission tomography. Ten male patients (mean age 32.4) fulfilling DSM-III-R criteria for schizophrenia were included in the study. Nine of these patients completed 4 weeks' treatment with ritanserin 10 mg b.i.d. The clinical effect was evaluated by means of CPRS and SANS and significant improvement was seen after 4 weeks' treatment both in positive and negative symptoms. Ritanserin was well tolerated and no extrapyramidal symptoms or akathisia were seen. Concentrations of monoamine metabolites and prolactin did not change during treatment. Ritanserin did not occupy D2-dopamine receptors. Thus, no indications of any D2-dopamine-antagonistic activity were obtained. All patients had expected ritanserin levels in plasma during the whole study. This first study of a selective serotonin-2 antagonist in the treatment of acute schizophrenic patients demonstrated significant clinical effects. However, the open design of the study does not allow us to conclude with any certainty that the patients' improvement was due to a specific blockade of serotonin-2 receptors or unspecific factors, although a direct D2-dopamine blockade could be ruled out.

Ritanserin and alcohol abuse and dependence.

Ritanserin is a potent long-acting 5-HT2 antagonist that acts centrally. In humans, ritanserin increases deep slow wave sleep, improved liveliness in a variety of psychiatric disorders and facilitated participation in behaviour therapy. During clinical trials unexpected observations indicated that ritanserin may be of value in treating drug addicts. Furthermore, initial clinical observations confirmed the efficacy of ritanserin in the chronic withdrawal phase after detoxification from ethanol. In the present paper, four experiments which support the potential of ritanserin as a pharmacological treatment for alcohol abuse and dependence are described. Firstly, ritanserin has been demonstrated to lack abuse potential and any direct interaction with ethanol. Secondly, in various models ritanserin has been shown to reduce alcohol intake and preference. The level of activity varies to some degree depending on the test and treatment procedure, as well as on the animal strain used. Long term ritanserin-related efficacy was illustrated by the gradual increase in alcohol drinking after cessation of the ritanserin treatment. Thirdly, the dopaminergic pathway and the nucleus accumbens have been shown to play a role in the effects of ritanserin. Finally, ritanserin reduces some alcohol withdrawal signs. Based on these findings, a clinical development plan started. After safety-interactions studies, ritanserin was demonstrated to influence the desire to drink in normal volunteers who display heavy social drinking. Currently, three major trials in 900 alcohol-dependent patients with different levels of dependence are running.

Ritanserin, imipramine, and placebo in the treatment of dysthymic disorder.

Fifty outpatients with dysthymic disorder (DSM-III) were divided by double-blind randomized assignment into three groups given ritanserin, imipramine, and placebo, respectively. The trial was of 7 weeks' duration; by week 6, imipramine was clearly superior to placebo, whereas by week 7, both drugs caused significantly more improvement than the placebo. Although imipramine had slightly greater efficacy than ritanserin, it also had significantly more side effects. This was particularly evident in the higher dropout rate with imipramine. The efficacy and side effect profile of ritanserin makes it well tolerated and acceptable with dysthymic patients who, although they do not respond as quickly as patients with major depressive disorder, do show significant improvement, given sufficient time.

Effect of ritanserin, a highly selective 5-HT2 receptor antagonist, on Parkinson's disease.

There is both experimental and clinical evidence to suggest a role for 5-hydroxytryptamine (5-HT) in Parkinson's disease. The effect of ritanserin, a highly selective 5-HT2 receptor antagonist, on Parkinsonian symptomatology was investigated in 10 patients in a single-blind placebo-controlled study. Akinesia and gait improved significantly in a dose-dependent manner in 5 and 7 patients respectively. However there was no significant improvement in tremor. The effects of ritanserin on akinesia and gait are consistent with a role for 5-HT in Parkinson's disease.