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It has been suggested that serotonin (5-HT) may be implicated in functional recovery after stroke; however, the underlying molecular mechanisms remain unknown. Here, the role of 5-HT was verified using ritanserin, a potent 5-HT2A receptor antagonist, and protein expression and modification were analyzed to further understand the association between paralysis recovery and molecular mechanisms in the brain. Experimental cerebral cortex infarctions were induced by photothrombosis in rats. Voluntary exercise was initiated 2 days after surgery. Motor performance was then measured using the rotarod test. Differences in protein expression and phosphorylation in the perilesional cortex were analyzed using western blot. In behavioral evaluations, performance in the rotarod test was significantly increased by exercise. However, there was a significantly lower value in time until falling after combined exercise and ritanserin administration compared with that of exercise alone. Protein expression analysis revealed that phosphorylation of protein kinase C (PKC) α, PKCε, and growth-associated protein 43 (GAP43) was significantly upregulated by exercise. These effects were attenuated by ritanserin administration. These data suggest that 5-HT may be related to the underlying mechanisms of exercise-dependent paralysis recovery, that is, exercise-dependent plasticity through the phosphorylation of PKC and GAP43.

Progressive multifocal encephalopathy (PML) caused by JC virus was frequently encountered in AIDS patients before combination antiretroviral therapy (cART). Incidence decreased and the outcome improved with cART. The immune reconstitution with cART is beneficial for HIV-infected patients and is an effective treatment for PML. However, when it is excessive an inflammatory response immune syndrome might occur with deterioration of PML. So far, no specific therapy has proven efficacious in small clinical trials in spite of some optimistic case reports. Combination of drugs targeted at different stages of JC virus life cycle seems to have a better effect. Passive and active immune therapies, immune competence "boosters" appear promising. New future approaches such as gene editing are not far away.

Earlier studies have demonstrated that the agonists of the mGlu(2/3) receptors produced anxiolytic actions after peripheral administration. However, the mechanism of their action is still not clear. Therefore the aim of the present study was to specify the role of the GABAergic and serotonergic system in the mechanism of the anxiolytic activity of group II mGlu receptor activators by using the stress induced hyperthermia test (SIH) in singly housed mice. We used an orthosteric mGlu(2/3) receptor agonist, LY379268, which induced anti-hyperthermic efficacy in the doses of 1-5mg/kg (73% of inhibition after a highest dose). The effect of the second ligand used, a mGlu(2) receptor positive modulator (PAM), LY487379, was observed in a dose range of 0.5-5mg/kg and reached 53% of the inhibition. The blockade of GABAergic system by GABA(A) receptor antagonist flumazenil (10mg/kg) or GABA(B) receptor antagonist CGP55845 (10mg/kg), and the blockade of serotonergic system by 5-HT(1A) receptor antagonist WAY100635 (0.1 and 1mg/kg) or 5-HT(2A/2C) receptor antagonist ritanserin (0.5mg/kg) had no influence on the anti-hyperthermic effect induced by effective dose of LY379268. However, the action of the effective dose of LY487379 was enhanced when co-administered with flumazenil, WAY100635 (0.1mg/kg) and ritanserin. Similar results were observed for the subeffective dose of LY379268 (0.5mg/kg). WAY100635 in a dose of 1mg/kg did not induce any enhancing effect on the activity of compounds. Therefore, it seems that the antagonism towards GABA(A) receptors, presynaptic 5-HT(1A) and postsynaptic 5-HT(2A/2C) receptors is responsible for the phenomenon. This article is part of a Special Issue entitled 'Anxiety and Depression'., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Clinical observations have suggested that ritanserin, a 5-HT(2A/C) receptor antagonist may reduce motor deficits in persons with Parkinson's Disease (PD). To better understand the potential antiparkinsonian actions of ritanserin, we compared the effects of ritanserin with the selective 5-HT(2A) receptor antagonist M100907 and the selective 5-HT(2C) receptor antagonist SB 206553 on motor impairments in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-treated mice exhibited decreased performance on the beam-walking apparatus. These motor deficits were reversed by acute treatment with L-3,4-dihydroxyphenylalanine (levodopa). Both the mixed 5-HT(2A/C) antagonist ritanserin and the selective 5-HT(2A) antagonist M100907 improved motor performance on the beam-walking apparatus. In contrast, SB 206553 was ineffective in improving the motor deficits in MPTP-treated mice. These data suggest that 5-HT(2A) receptor antagonists may represent a novel approach to ameliorate motor symptoms of Parkinson's disease., (Published by Elsevier Ltd.)

It was reported that ritanserin, a 5HT2A/2C antagonist, improves negative symptoms when added to neuroleptics in inpatients with predominantly negative symptoms. Nevertheless, the results of published studies are contradictory so far. This study was designed to investigate the effect of ritanserin added to risperidone as augmentation therapy in patients with chronic schizophrenia and prominent negative symptoms in a double blind and randomized clinical trial. Eligible participants in this study were 40 patients with chronic schizophrenia. All patients were inpatients and were in the active phase of the illness, and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion, 20 to risperidone 6 mg/day plus ritanserin 12 mg/day (6 mg bid) and 20 to risperidone 6 mg/day plus placebo. The principal measure of the outcome was Positive and Negative Syndrome Scale (PANSS). Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of risperidone and ritanserin showed a significant superiority over risperidone alone in decreasing negative symptoms and PANSS total scores. The present study indicates ritanserin as a potential adjunctive treatment strategy for the negative symptoms of schizophrenia. Nevertheless, results of larger controlled trials are needed, before recommendation for a broad clinical application can be made.

The past decade has seen an expansion of research and knowledge on pharmacotherapy for the treatment of alcohol dependence. The Food and Drug Administration (FDA)-approved medications naltrexone and acamprosate have shown mixed results in clinical trials. Oral naltrexone and naltrexone depot formulations have generally demonstrated efficacy at treating alcohol dependence, but their treatment effect size is small, and more research is needed to compare the effects of different doses on drinking outcome. Acamprosate has demonstrated efficacy for treating alcohol dependence in European trials, but with a small effect size. In U.S. trials, acamprosate has not proved to be efficacious. Research continues to explore which types of alcohol-dependent individual would benefit the most from treatment with naltrexone or acamprosate. The combination of the two medications demonstrated efficacy for treating alcohol dependence in one European study but not in a multi-site U.S. study. Another FDA-approved medication, disulfiram, is an aversive agent that does not diminish craving for alcohol. Disulfiram is most effective when given to those who are highly compliant or who are receiving their medication under supervision. Of the non-approved medications, topiramate is among the most promising, with a medium effect size in clinical trials. Another promising medication, baclofen, has shown efficacy in small trials. Serotonergic agents such as selective serotonin reuptake inhibitors and the serotonin-3 receptor antagonist, ondansetron, appear to be efficacious only among certain genetic subtypes of alcoholic. As neuroscientific research progresses, other promising medications, as well as medication combinations, for treating alcohol dependence continue to be explored.

The protective effect of 5-HT(2) receptor blockade with ketanserin or ritanserin against cadmium liver injury was investigated. Male Wistar rats were injected intraperitoneally with a sublethal dose of cadmium (3.5 mg/kg body weight). Rats were treated with normal saline (group I), ketanserin (3 mg/kg body weight; group II), or ritanserin (3 mg/kg body weight; group III) 2 hr prior and 4 hr after cadmium administration and killed at different time points. Hematoxylin/eosin-stained liver sections were assessed for necrosis, apoptosis, peliosis, mitoses, and inflammatory infiltration. Apoptosis was also quantified by the TUNEL assay. Nonparenchymal liver cells and activated Kupffer cells were identified histochemically. Necrosis, hepatocyte apoptosis, nonparenchymal cell apoptosis, and macroscopic and microscopic peliosis were markedly reduced or minimized in ketanserin- or ritanserin-treated rats. The observed protective effect was almost identical for both ketanserin and ritanserin administration. 5-HT(2) receptor blockade exerts a protective effect against acute cadmium-induced hepatotoxicity.

Administration of benzodiazepines is known to be associated with tolerance and a withdrawal syndrome on abrupt cessation. The aetiology of the withdrawal syndrome is not known but a role for the serotonin (5HT) system is suspected. The aim of the current study was to investigate the usefulness of 5-HT2 antagonists in the treatment of benzodiazepine withdrawal syndrome in the rat. Male Wistar rats were treated with either diazepam (4 mg/kg) or vehicle for 14 days, then abruptly withdrawn for 24h. Animals were tested in the social interaction paradigm and elevated plus maze. Some diazepam-withdrawn rats were pre-treated with 5HT2 antagonists 60 min before behavioural testing. Acute withdrawal from benzodiazepines significantly reduced social interaction between pairs compared to vehicle or diazepam-treated animals. Similarly, for the elevated plus maze withdrawn animals made fewer entries and spent less time on the open arms than did vehicle or diazepam-treated animals. Single doses of 5-HT2 antagonists, mianserin (5mg/kg) and ritanserin (1mg/kg), effectively ameliorated withdrawal anxiety in the rat, returning behavioural function in the social interaction test and elevated plus maze to levels comparable to vehicle-treated animals.

Early microvascular constriction following atherosclerotic plaque rupture may be mediated via serotonin and/or endothelin-1. Atherosclerotic lesions in the rabbit hindlimb underwent plaque rupture, resulting in a rapid reduction of distal flow (7.1+/-0.7 ml/min pre-rupture versus 3.6+/-0.6 ml/min post-rupture, P<0.001) and a rise in distal microvascular resistance (10.5+/-0.9 mm Hg min/ml pre-rupture versus 23.5+/-3.5 mm Hg min/ml post-rupture, P=0.01). Distal microvascular resistance remained elevated following endothelin-1 receptor antagonism and control vehicle, but normalised after serotonin receptor antagonism with ritanserin (10.5+/-0.9 mm Hg min/ml pre-rupture versus 22.2+/-6.0 mm Hg min/ml post-endothelin-1 receptor antagonism [P<0.05] versus 21.6+/-6.2 mm Hg min/ml post-control vehicle [P<0.05] versus 11.6+/-2.0 mm Hg min/ml post-ritanserin [P=NS]). Early antagonism of serotonin receptors protects against distal microvascular constriction following atherosclerotic plaque rupture.

The effect of subchronic co-administration of ritanserin (1.5 mg/kg, i.p., twice a day) and haloperidol (1 mg/kg, i.p., twice a day) on rat vacuous chewing movements and on tyrosine hydroxylase-immunostaining was investigated. Ritanserin significantly reduced rat vacuous chewing movements observed following 2, 3 and 4 weeks of haloperidol administration and after 5 days of haloperidol withdrawal. Furthermore, ritanserin prevented the reduction of striatal tyrosine hydroxylase-immunostaining and the shrinkage of nigral dopaminergic cell bodies induced by haloperidol. The present results indicate that ritanserin may possess protective properties on both dopaminergic nigro-striatal neuron alterations and vacuous chewing movements induced by haloperidol, and provide further evidence indicating a possible association between these two haloperidol-induced effects.

A recent study in narcolepsy patients has shown that ritanserin, a 5HT2-antagonist, reduced wake after sleep onset times and subjective sleepiness during daytime. To assess the efficacy of this compound in a statistically sufficient number of narcoleptic patients a double-blind, placebo-controlled, European multi-center study on the effects of ritanserin on daytime sleepiness, the feeling of being refreshed in the morning, number of unwanted sleep periods and slow-wave sleep was performed. All 134 narcolepsy patients were allowed to remain on stable concomitant antidepressant, stimulant and gammahydroxybutyrate medication during the trial. Patients were randomly assigned to treatment with 5 mg or 10 mg ritanserin or placebo given once daily for 28 days. Efficacy was measured by two 40-hour polysomnographic recordings, visual analogue scales and physician, partner, parents and patient-rated sleep-wake behavior tests prior to and after the trial. Patients kept diaries on sleepiness, numbers of wanted and unwanted sleep periods, feeling of being refreshed and frequency of narcoleptic symptoms during the entire treatment period. Treatment with 5 and 10 mg ritanserin significantly improved the 'feeling of being refreshed in the morning,' but no other narcoleptic symptoms as assessed in the diary. Whereas investigators had the impression that the primary efficacy parameters were not improved by ritanserin, patients reported significant improvements in four out of six parameters, and patients partners in two out of six parameters with 5 mg ritanserin compared to placebo. Both ritanserin doses resulted in a significant increase of nocturnal slow-wave sleep (percentage of total sleep time) and a significant, dose-dependent reduction in NREM stage 1 percentage during daytime sleep. The significant polysomnographic findings were not paralleled by changes in the subjective parameters daytime sleepiness or number of unplanned sleep periods. In contrast to the first study on narcoleptic patients, ritanserin only improved one subjective parameter, but did not improve objective sleep quality or number of "sleep attacks" or reduce "wake after sleep onset" during night or daytime sleep. In conclusion, ritanserin may serve as add-on medication for the treatment of impaired sleep quality in narcoleptic patients, but not as a stimulant or hypnotic type of medication.

Background: Bipolar disorder is a lifelong episodic condition characterized by mood swings between mania and depression. Several lines of evidence suggest that serotonin is likely to play a pivotal role in the pathophysiology of bipolar disorder. Ritanserin, a 5-HT2 receptor antagonist, has been reported to have antipsychotic activity. In this 6-week double blind, placebo controlled study involving moderate to severe manic patients, we assessed the effects of ritanserin plus haloperidol in combination with lithium., Methods: 45 patients aged between 21-43 were eligible to participate as they met the DSM-IV criteria for a current manic episode, on the basis of a clinical interview by an academician psychiatrist. In addition, a score of at least 20 points on the Young Mania rating Scale was required representing moderate to severe mania. Patients were randomly allocated lithium (1-1.2 mEq/L) + haloperidol (10 mg/day)+ ritanserin (10 mg/day) (Group A) or lithium (1-1.2 mEq/L)+ haloperidol (10 mg/day) + placebo (Group B) for a 6-week, double-blind, placebo-controlled study. Patients were assessed by a third year psychiatry resident at baseline and 3, 7, 14, 21, 28 and 42 days after the medication started. All patients entered the hospital were not previously under any medication. The mean decrease in the Young Mania Rating Scale score from baseline was used as the main outcome measure of response of mania to treatment. The extrapyramidal symptoms were assessed using the Extrapyramidal Symptoms Rating Scale. Side effects were systematically recorded throughout the study and were assessed using a checklist., Results: Young Mania Rating Scale total scores improved with ritanserin. The difference between the two protocols was significant as indicated by the effect of group and the between-subjects factor (F = 5.02, d.f. = 1, P = 0.03). The means Extrapyramidal Symptoms Rating Scale scores for the placebo group were higher than the ritanserin group and the difference was significant in day 42. The difference between the two groups in the frequency of side effects was not significant, Conclusions: The efficacy of ritanserin to obtain a better improvement in patients with mania seems to support the 5-HT hypothesis of bipolar disorder.

Background: Dysthymia is a prevalent form of subthreshold depressive disorder, associated with considerable disability and high co-morbidity. This paper systematically appraises the evidence for the efficacy and acceptability of the pharmacological treatment for this condition., Methods: Randomised, controlled trials evaluating the efficacy of drug therapies for dysthymia were included. A comprehensive search of the literature was performed, aiming to avoid publication bias. Pooled relative risks (RR) and 95% CIs were calculated with the Random Effect Model method. The number needed to treat (NNT) and number needed to harm (NNH) were estimated for statistically significant results., Results: Twenty-five trials were included for the main comparisons. Regarding placebo-controlled trials (n = 16), similar results were obtained in terms of efficacy for different groups of drugs, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs) and other drugs (sulpiride, amineptine, and ritanserin). The pooled RR for treatment response was 0.68 (95% CI 0.57-0.81) for TCA and the NNT was 4.3 (95% CI 3.2-6.5); 0.68 (95% CI 0.56-0.82) for SSRIs (NNT 5.1; 95% CI 3.9-7.7); 0.59 (95% CI 0.48-0.71) for MAOIs (NNT 2.9; 95% CI 2.2-4.3). Other drugs (amisulpride, amineptine and ritanserin) showed similar results. The equivalent efficacy between antidepressants as found in trials where active medications were compared confirmed the efficacy findings from placebo trials. In general, patients treated with a TCA were more likely to report adverse events, compared with placebo and SSRIs., Conclusions: Pharmacotherapy for dysthymia appears to be an effective short-term treatment for dysthymic disorder. Newer antidepressants are equally effective and have better acceptability than TCAs, although their higher cost must be balanced against this assumed advantage.

Rationale: Serotonin-2 (5-HT(2)) receptor antagonism has been hypothesized to have antipsychotic activity. However, there has been limited evidence directly linking 5-HT(2) receptor antagonism to symptom control in schizophrenic patients., Objectives: In order to test this hypothesis this study evaluated the capacity of pretreatment with the 5-HT(2) receptor antagonist ritanserin to attenuate the effects of the 5-HT agonist, m-chlorophenylpiperazine (mCPP)., Methods: Twenty-two male inpatients who met DSM-III-R criteria for schizophrenia or schizoaffective disorder completed 4 test days during which 10 mg ritanserin or matched placebo was administered orally 50 min prior to the intravenous infusion of 0.1 mg/kg mCPP or saline. The test days were conducted in a randomized order under double-blind conditions., Results: mCPP mildly and transiently increased positive symptoms and behavioral activation but not negative symptoms, as assessed by the Brief Psychiatric Rating Scale. mCPP also raised plasma prolactin and cortisol levels. All of these effects were attenuated by ritanserin pretreatment., Conclusions: These data support a contribution of 5-HT(2) receptor stimulation to symptom exacerbation in schizophrenic patients and a role for 5-HT(2) receptor antagonism in the prevention of this effect.

Neuroscientific underpinnings and pharmacotherapeutic treatments of substance use disorders are rapidly developing areas of study. In particular, there have been exciting new developments in our understanding of the involvement of excitatory amino acid neurotransmitter systems and the opiate and serotonin systems in the pathophysiology of alcohol withdrawal, alcohol dependence, and in subtypes of individuals with alcoholism. In this article, new developments in the pharmacotherapy of alcohol dependence will be reviewed. In particular, the use of anticonvulsants in alcohol withdrawal and protracted abstinence syndromes will be discussed. New data on opiate antagonists and acamprosate, an agent that exerts actions through excitatory amino acid systems in relapse prevention, will be reviewed. Finally, there will be a review of new data concerning the use of serotonin reuptake inhibitors in subtypes of alcoholism and the use of combination pharmacotherapy.

Eighty cocaine-dependent individuals enrolled in outpatient treatment took part in a randomized, double-blind, placebo-controlled trial of ritanserin, a 5-HT(2) antagonist, as an adjunct therapy. Participants attended an outpatient day hospital therapy program each day and received tablets containing placebo or 10 mg ritanserin for a 4-week period. Primary outcome measures included retention in treatment, urine drug tests, and self-reports of craving. Secondary outcome measures were depression scores on the Beck and Hamilton inventories, negative mood as measured by the Profile of Mood States, and life functioning as measured by the Addiction Severity Index. Although participants showed improvement over the 4 weeks, there were no group differences on any of the measures. These results fail to support the use of ritanserin as a complement to outpatient psychosocial therapy for cocaine dependence.

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.

This study investigated the ability of ritanserin, a 5-HT2 antagonist, to modify ethanol withdrawal (EW) symptoms in two animal models of anxiety: the elevated plus-maze (EPM) and the pentylenetetrazol (PTZ) discrimination assay. Long-Evans hooded rats were given a nutritionally balanced liquid diet containing 4.5% ethanol for 10 days. Twelve hours after removal of the ethanol diet, rats were tested in the EPM. A significant reduction in the open-arm activity and the number of total arm entries was observed, which is indicative of EW. Acute ritanserin (0.16-0.64 mg/kg, i.p., 60 min) had no effect on EW-induced anxiety-like behavior on the EPM. Ritanserin (0.08-0.64 mg/kg, i.p., b.i.d. 12 h) administered concurrently with the last 5 days of ethanol diet produced an increase in the time spent on the open arms of the EPM and reversed the EW-induced reduction in total arm entries. Rats trained to discriminate between saline and PTZ (an anxiogenic drug), selected the PTZ lever during EW. Chronic ritanserin (0.32 mg/kg, i.p., b.i.d. ) did not block PTZ lever responding during EW. On the rotorod, ritanserin (0.32 mg/kg, i.p.) increased the motor incoordination induced by ethanol. In conclusion, coadministration of ritanserin with ethanol prevented the development of EW-induced anxiety as measured by the EPM, but not in the PTZ drug discrimination.

Eighty-one cocaine-dependent outpatients were assessed for their reactions to cocaine-related cues in a laboratory setting. All subjects contributed a urine sample prior to the session. Compared with non-drug control cues, the cocaine stimuli produced increases in physiological arousal, self-reports of high, craving, and withdrawal, and self-reports of negative mood. Subjects who tested cocaine-positive on the day of testing differed only in skin resistance responding from those who tested cocaine-negative. Changes in cue-induced physiological and self-report measures were also not associated with between-subject variations in mood as measured by the Profile of Mood States (POMS) questionnaire administered prior to cue assessment. Thus, variations in baseline mood and recent cocaine use history do not introduce an additional source of variability in cue reactivity measurements. However, negative mood states at the start of a session were associated with higher levels of self-reported craving, high, and withdrawal both before and after cue exposure.

Rats were given two weeks of home cage access to either "near-beer" (a beverage that tastes like beer but contains <0.5% ethanol v/v) or near-beer with added ethanol (4.5% v/v), which is simply referred to as "beer". The two groups of rats (near-beer and beer) were then trained on a "lick-based progressive ratio paradigm" in operant chambers in which an ever increasing number of licks had to be emitted for each successive fixed unit of near-beer or beer delivered. Break points (the ratio at which responding ceased) for near-beer and beer were approximately equal under baseline conditions. Rats were then tested for the effects of the 5HT2A/2C receptor antagonist ritanserin (0.625, 2.5 or 10 mg/kg), the opioid receptor antagonist naloxone (0.625, 2.5 or 10 mg/kg) or the cannabinoid CB1 receptor antagonist SR 141716 (0.3, 1 or 3 mg/kg). All three drugs caused a dose-dependent reduction of break-points and locomotor activity in both the beer and near-beer groups. However, the effects of SR 141716 and naloxone, but not ritanserin, on breakpoints were significantly more pronounced on rats drinking beer compared to those drinking near-beer. There were no such differential effects of any of the drugs on locomotor activity across the two groups. These results suggest that both SR 141716 and naloxone differentially affect the motivation to consume alcoholic beverages and may thus have potential as drugs for the treatment of alcohol craving.

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.

It has been proposed that the reversal of serotonin-mediated vasoconstriction accounts for the neuroprotective effect of serotonin (5-HT2) receptor blockade in focal cerebral ischemia. We investigated the effect of pretreatment with ritanserin, a 5-HT2 receptor antagonist, on cerebral blood flow in a model of photothrombotic middle cerebral artery occlusion in rats. Local cerebral blood flow was measured by iodoantipyrine autoradiography 30 minutes after induction of ischemia. Using a novel image-alignment algorithm, 3-dimensional reconstructions of averaged cerebral blood flow were calculated. The difference-image of local cerebral blood flow between ritanserin and vehicle-treated animals revealed a subcortical zone underlying the ischemic cortex where cerebral blood flow was markedly enhanced indicating a beneficial hemodynamic effect of ritanserin. Three-dimensional image analysis provides a powerful tool to detect inter-group differences of cerebral blood flow which are underestimated by conventional types of data analysis.

The aim of the study was to evaluate in a double-blind manner the effect of the long-acting 5-hydroxytryptamine 2 (5-HT2)-receptor blocker Ritanserin on clinical symptoms in patients with fibromyalgia syndrome (FM) and on production of antibodies to serotonin, gangliosides and phospholipids, recently shown to have a high incidence in this disease. Fifty-one female patients with typical FM were included in the 16-week study: 24 received Ritanserin and 27 received a placebo. Antibodies to 5-HT, gangliosides (Gm1) and phospholipids (thromboplastin) were determined by enzyme-linked immunosorbent assay at day 0 and at the end of week 16. The psychological and physical status, including tender points, of the patients was evaluated at day 0 and at the end of weeks 4 and 16. At the end of the study, there was an improvement (p < 0.05) in feeling refreshed in the morning in the Ritanserin-treated group and headache was also significantly improved compared with the placebo group. There was no difference in pain, fatigue, sleep, morning stiffness, anxiety and tender point counts in the Ritanserin and placebo groups. Fifty-one per cent of the 51 patients had at least one of the three antibodies to 5-HT, Gm1 and phospholipids. The incidence and activity of these antibodies were not influenced by Ritanserin or placebo. The observation that Ritanserin has only a small effect on clinical symptoms indicates that disturbances in serotonin metabolism or uptake may be only one factor in the pathogenesis of the disease. The high incidence of a defined autoantibody pattern in FM could again be confirmed in this study. However, it remains speculative whether immunological reactions are, indeed, involved.

Sixty-five cocaine-dependent subjects were enrolled into a 10-week randomized, double-blind study to determine the safety and efficacy of the serotonin-2 receptor antagonist, ritanserin (10 mg/day), in reducing cocaine consumption and craving. All subjects also participated in a structured intensive outpatient psychosocial program. Seventy-three percent of the participants completed the treatment program and follow-up. Subjects experienced a significant reduction in craving: 66.4% and 32.5% for the placebo and ritanserin groups, respectively. These reductions in craving were not paralleled by substantial decreases in cocaine use. Self-reported cocaine use was less frequent in the placebo group; paradoxically, blood levels of its metabolite, benzoylecgonine, were also higher although insignificantly so. Generally, ritanserin was well tolerated but significantly prolonged the QTc interval on the electrocardiogram. This outpatient program is effective at maintaining cocaine-dependent individuals in treatment and reducing craving. Ritanserin (10 mg/day) is not an efficacious adjunct to psychosocial treatment for cocaine dependence.

The described dependence was formed in mice [correction of rats] by subcutaneous injections of morphine in doses growing from 10 to 100 mg/kg (8 days, twice a day). The effect of 5-HT2 receptor blocker ritanserine (1, 5, and 10 mg/kg) on expression of the abstinence syndrome (according to the behavioral and somato-autonomic parameters) 24 h after morphine discontinuation was studied. Ritanserine attenuated the manifestation of some abstinence parameters associated with activation of the serotonin system in formation of the dependence. The effect was less in expression of abstinence.

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.

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.

The 5-HT2 receptor antagonist, ritanserin, reduces alcohol intake in rats and the nucleus accumbens (NAC) has been proposed as a site of action for the drug. Recent microdialysis studies have shown that acute subcutaneous (SC) administration of ritanserin increases extracellular 5-HT levels in the NAC. The present study evaluated, in genetically heterogeneous rats with developed preference for 3% ethanol, whether the attenuation of ethanol intake induced by ritanserin might be related to its effect on the synaptic availability of 5-HT in the NAC. Damaging 5-HTergic neurons by intracerebroventricular infusion of 5,7-dihydroxytryptamine (5,7-DHT) abolished the effect of ritanserin on ethanol consumption. Injections of the 5-HT3 receptor antagonist MDL 72222 into the NAC significantly reduced the inhibitory effect of SC injection of ritanserin, 1 mg/kg, and completely abolished the effect of ritanserin, 0.1 mg/kg. Subcutaneous injections of MDL 72222, 0.3 mg/kg 3 times/day, suppressed the effect of SC ritanserin, 0.1 mg/kg. The present findings, together with those of previous experiments showing that the tryptophan hydroxylase inhibitor p-chlorophenylalanine abolishes the effect of ritanserin, support the hypothesis that its effect on ethanol intake may be due to increased synaptic availability of 5-HT into the NAC.

This article presents a current overview of the efforts to suppress pharmacologically the craving, dependence, or other factors associated with the self-selection of alcohol in an experimental animal. The contemporary status of the pharmacotherapy of experimental alcoholism similarly is described for different animal models of alcohol drinking. An evaluation is presented of several classes of drug for their efficacy in ameliorating the volitional ingestion of alcohol in the presence of an alternative fluid. Currently, two main experimental animal models of alcoholism are being used in this endeavor: (a) genetic lines or substrains of high alcohol preferring or high drinking rats; and (b) strains of nondrinking or low alcohol preferring rats which are induced chemically to prefer alcohol. Because of technical, methodological, and other issues surrounding the procedures used to assess the efficacy of a drug in reducing alcohol intake, several of the newer findings remain controversial. For example, serious side effects on the intake of food, caloric regulation, motor activity, or other functions would preclude the clinical utility of the drug. However, several drugs which affect monoaminergic neurons as well as opioid systems in the brain now seem to offer promise as agents which do possess clinical benefits. Two of these drugs, FG5606 (amperozide) and FG 5893 are essentially "antialcoholic" or anticraving and are without any significant side effects on cerebral mechanisms responsible for hunger, caloric intake, motor activity, or other physiological process. Amperozide, a 5-HT2 receptor antagonist with dopamine releasing properties, is particularly notable because of its irreversible nature in attenuating alcohol preference for months after its administration. It is concluded that future pharmacological research on presently available and newly developed compounds will provide exciting opportunities to the clinician who can utilize a particular drug as an adjunctive tool in the therapeutic treatment of the alcoholic individual.

We wished to characterize MDL 28,133A (1-(4-fluorophenyl)-2-[4-[(4-methanesulfonamidophenyl)carbonyl]-1- piperidinyl-ethanone HCl), a potent 5-HT2 receptor antagonist, on platelet aggregation and platelet thrombosis and determined its effect on thrombolysis with streptokinase (SK) in dogs with coronary thrombosis. MDL 28,133A and ritanserin, 0.3-1 microM, competitively inhibited 5-HT-induced platelet aggregation in dog platelet-rich plasma (PRP) in vitro. The pA2 values and slopes were 6.29 +/- 0.09, -0.96 +/- 0.14, and 6.58 +/- 0.09, =1.64 +/- 0.34 for MDL 28,133A and ritanserin, respectively, suggesting that both agents are similar in potency to 5-HT2 receptor antagonists. MDL 28,133A (0.01 mg/kg, p.o.) produced inhibition of arachidonic acid-induced platelet aggregation in whole blood from conscious dogs ex vivo for > or = 2 h, indicating oral bioavailability. The magnitude and duration of the effect of MDL 28,133A on platelet aggregation in whole blood was similar to that of ketanserin (2.5 mg/kg, p.o.). MDL 28,133A (0.001-0.03 mg/kg, i.v.) completely abolished cyclic flow reductions (CFRs) in stenosed and partially deendothelialized left anterior descending coronary arteries of anesthetized dogs for at least 120 min without affecting systemic blood pressure (BP) and heart rate, thus indicating that MDL 28,133A is a potent antithrombotic agent. Ketanserin (0.5 mg/kg, i.v.) also abolished CFRs, but produced a significant decrease in systemic BP as well. MDL 28,133A (0.001 mg/kg, i.v.) shortened time to reperfusion (15 +/- 1 vs. 36 +/- 8 min), prolonged time to reocclusion (112 +/- 6 vs. 85 +/- 6 min), and increased total volume reflow (20 +/- 2 vs. 10 +/- 2%) in dogs with coronary artery thrombosis undergoing thrombolysis with SK (1,000 U/min, i.a.). Reocclusion rate was not affected by MDL 28,133A (4 of 5 vs. 4 of 6). Treatment with heparin (150 U/kg, i.v. every hour for 2 h) alone or in combination with MDL 28,133A did not improve time to reperfusion but enhanced total volume reflow and prevented reocclusion. MDL 28,133A is a potent 5-HT2 receptor antagonist that inhibits platelet thrombosis and facilitates thrombolysis in vivo. The impeding effect of MDL 28,133A in coronary thrombosis and the lack of hemodynamic effects suggests that MDL 28,133A may be of benefit in treatment of hyperthrombotic conditions without having hemodynamic side effects.

During halothane-induced malignant hyperthermia (MH), plasma levels of serotonin (5-hydroxytryptamine, 5-HT) increase in pigs. Administration of 5-HT agonists which stimulate the 5-HT2A subreceptor triggers MH in susceptible pigs. A possible link between MH induced by 5-HT2A receptor agonists and halothane could be an increase of second messengers such as phosphoinositides (inositol polyphosphates), which have recently been implicated in the abnormal regulation of skeletal muscle calcium release in MH. If so, antagonists of 5-HT2A receptors which are linked to phosphoinositide turnover should be capable of preventing, retarding or attenuating halothane-induced MH. This possibility was investigated in the present study in MH susceptible pigs, using dantrolene for comparison, Development of MH triggered by a halothane challenge (inhalation of 3% halothane for 15 min) was completely prevented by dantrolene, 3.5 mg/i.v., whereas the 5-HT2A receptor antagonists ritanserin (0.5-10 mg/kg i.v.) or ketanserin (0.5-10 mg/kg i.v.) exerted no prophylactic effect. In pigs in which dantrolene, ritanserin or ketanserin where given in combination with hyperventilation after development of MH, dantrolene exerted therapeutic efficacy, whereas neither ritanserin nor ketanserin were effective treatments. The data indicate that 5-HT is not critically involved in the mechanisms of halothane-induced MH, at least under the conditions of the present experimental study.

The use of vasodilators to prevent the rupture of esophagic varices (EV) due to portal hypertension (PH) would reduce the portal pressure (PP) as the result of increased portocolateral flow. Rinsaterine, a 5-HT2 receptor blocker, reduces PP in experimental models of PH. This pilot study was designed to verify if ritanserine has a sustained and additive effect to propranolol on PP in cirrhotic patients with PH. Ten chronic patients with EV, under prophylactic therapy with propranolol and with a suprahepatic venous pressure gradient (SVPG) > 12 mm Hg, received ritanserine (0.11-0.14 mg/kg/day). One patients completed one month of treatment due to drug intolerance. Nine patients completed one month of treatment; SVPG did not show any significant variation in four patients and decreased 3 mm Hg in five patients, which were treated during 70 days more. After then, HVPG returned to its previous values except in one patient. The long-term association between ritanserine and propranolol does not improve the results of propranolol. However, the initial response observed in all of these patients supports the role of the serotoninergic system in the PH and states the need for further studies on 5-HT2 blocking for the prophylaxis of EV rupture.

In studies by means of the Swedish version of the Positive and Negative Syndrome Scale, we have demonstrated a 5-factor model of schizophrenia, including positive, negative, excited, anxious/depressive and cognitive factors. In this study, the 5 factors were correlated with background factors in a series comprising 140 patients with schizophrenic syndromes. None of the 5 factors revealed any significant age or sex differences. The positive factor correlated positively with the number of previous hospitalizations and the negative factor correlated negatively. The excited factor correlated negatively with age at onset, age at first hospitalization and positively with the duration of the illness and the number of previous hospitalizations. The cognitive factor correlated negatively with age at onset and age at first hospitalization and positively with the duration of the illness. Age at onset was positively correlated with delusions, excitement, unusual thought content and poor impulse control and negatively with lack of spontaneity. The duration of illness correlated positively with excitement, difficulty in abstract thinking and mannerisms. The number of previous hospitalizations correlated positively with delusions, excitement, unusual thought content and poor impulse control and significant negative correlations were demonstrated as concerns blunted affect and lack of spontaneity.

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.

For a number of years, dysthymia was considered to be non-responsive to antidepressant treatment. During the last decade, early studies with tricyclic antidepressants (TCAs) demonstrated the superiority of the TCAs over placebo. The side effect profile of the TCAs and the moderate degree of symptomatology resulted in reduced compliance and thus to the clinical impression of lack of efficacy. The newest generation of antidepressants, the SRRIs and the RIMAs, with their more acceptable side effect profiles, allowed for the adequate evaluation of pharmacotherapy in dysthymia. The initial open studies with SSRIs indicate a clear efficacy of this group of antidepressants. Likewise, a 5HT2 antagonist, ritanserin, has been shown to be superior to placebo. More recently, a large placebo-controlled study of moclobemide, a RIMA, clearly demonstrated the superiority of this drug over placebo. Based on this evidence, it is now appropriate to consider antidepressants as a clearly effective method of treating dysthymia.

Therapeutic drug development in alcoholism could be targeted at any of the following: direct antagonism, substitution, treatment of abstinence, enhancement of aversion, modification of biodisposition, or craving. Ritanserin is a potent, centrally acting, highly selective 5-HT1C/2 antagonist which, in addition to having a sleep-regulating and anti-depression/anti-axiety effect, displays a unique pharmacological action in several animal paradigms of substance abuse which assess drug-craving. In fact, the latter pharmacological action was demonstrated after initial clinical observations suggested an effect of ritanserin in the chronic withdrawal phase after detoxification from alcohol in patients. The results of a recent double-blind, placebo-controlled, trial indicated that ritanserin did not induce aversion to drink alcohol in normal volunteers who display social drinking, but are not suffering alcohol dependence. Currently, a full clinical development program of ritanserin in cocaine and alcohol abuse is ongoing. Three major double-blind, placebo-controlled trials in alcohol dependent patients are in progress. Patients of different severity levels, ranging from mild to very severe, are studied. The dosages of ritanserin tested (2.5 mg, 5 mg, and 10 mg o.d.) are known to be well tolerated and safe. Two trials aim for relapse prevention--clinically defined in one, biochemically defined in the other-, and one trial has improved (reduced) drinking behaviour as a therapeutic goal. This program, which involves close to 900 alcohol-dependent patients, is well under way, and is still picking up momentum.

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.

The effectiveness of ritanserin, a selective 5-HT2 and 5-HT1c antagonist, in reducing negative symptoms in schizophrenia was investigated in a double-blind, placebo-controlled trial. Trial treatment was added to a stable neuroleptic treatment in 33 schizophrenic patients with predominantly negative symptoms. Ritanserin reduced the negative symptoms, as measured with the SANS. The main reduction was for the items facial expression, global affective flattening, and relationships with friends and peers. Also a reduction in total BPRS score was found, which approached statistical significance. Significant reductions were observed for the BPRS items emotional withdrawal and depressive mood. Ritanserin or other drugs blocking 5-HT2 and/or 5-HT1c receptors could be important in reducing specific symptoms in schizophrenic patients.

Ritanserin (0.5 and 1 mg/kg) and ketanserin (2.5 mg/kg), two antagonists with high affinity for 5-HT2 receptors, attenuated restraint stress-induced hypophagia in rats. Two injections of the 5-HT2 receptor antagonist cinanserin (30 nmol/0.5 microliter) in the paraventricular nucleus of the hypothalamus completely reversed the effect of stress on food intake. (+/-)Cyanopindolol (3 and 8 mg/kg), an antagonist at 5-HT1A and 5-HT1B receptors, had no effect whereas 8-hydroxy-2-di-n-propylamino)tetralin (30-300 micrograms/kg), an agonist at 5-HT1A receptors, significantly attenuated the hypophagia. The results suggest that restraint stress-induced hypophagia is mediated by 5-HT2 receptors in the paraventricular nucleus of the hypothalamus. The potential utility of this model in anorexia nervosa is discussed.

Ritanserine had a positive effect on children with Rett's syndrome and children with autistic syndrome and mental retardation. The most marked effect was observed in reduction of psychomotor instability, impaired concentration of attention and partly also in autism.

The new potential anxiolytic ritanserin was studied in a double-blind manner vs. alprazolam, diazepam and placebo in 23 healthy subjects. The subjects belonged either to a high anxiety level group or a low anxiety level group, in order to study the effect of the anxiety level on the pharmacodynamic responses. The assessments included cognitive function (memory tests), psychomotor performance [Critical Flicker Fusion (CFF), Choice Reaction Time (CRT)], subjective ratings of alertness and overnight sleep and stress paradigm. Ritanserin (10 mg), alprazolam (0.75 mg), diazepam (10 mg) and placebo were given as single oral doses following a latin square design. Groups were well contrasted on the Cattell anxiety scale and were not overlapping. On no psychometric variable have there been any interactions between the anxiety level and the drug factor. At baseline an anxiety-related difference between the two groups was observed: lower CFF value in the high anxiety group (-1.4 Hz). Both benzodiazepines impaired psychomotor assessment and memory function and increased sleepiness. Ritanserin decreased CFF values without significantly affecting CRT on which nevertheless a trend to impairment was observed. Memory tests, and subjective ratings of alertness were unaffected by ritanserin. A trend to an antistress effect was observed on electrodermogram after ritanserin. Both benzodiazepines decreased central nervous system arousal and memory while ritanserin was inactive except on CFF. Recent data support the hypothesis that 5-HT2 blockers decrease pupil diameter which is a well known covariate of flicker frequency.

We recently reported that ritanserin, a 5-hydroxytryptamine receptor antagonist, induced significant reduction of portal pressure in cirrhotic rats. In this study, we investigated the hemodynamic effects of a combination of propranolol and ritanserin in conscious and unrestrained cirrhotic rats. Heparinized catheters exiting from the neck were placed into the portal vein, inferior vena cava, aorta and left ventricle. Cardiac output and regional blood flows were measured with radiolabeled microspheres and the reference-sample method. Serial hemodynamic studies were performed 4 hr after rats awakened (basal), 1 hr after administration of ritanserin (0.63 mg/kg body wt, intravenously) and after intravenous propranolol infusion (0.33 mg/kg/min for 15 min) in nine cirrhotic rats. Similar measurements were obtained in a control group of eight cirrhotic rats treated with the solvents of ritanserin and propranolol. Ritanserin caused significant reduction of portal pressure (-19%). Portal-venous inflow and splanchnic arteriolar resistances remained unchanged, whereas portal-venous resistances were slightly but significantly lowered (-17%); and ritanserin had no effects on systemic hemodynamics. The addition of propranolol resulted in further reduction of portal pressure (-24%); the final reduction after combined therapy was -38%. Propranolol induced a marked decrease in cardiac output (-31%) and portal-venous inflow (-30%). It also caused a significant increase in splanchnic arteriolar resistance (+39%), but did not magnify the ritanserin-induced decrease of portal-venous resistance. The combined therapy did not modify the mean arterial pressure. Our results show that the effects of ritanserin on portal pressure--probably mediated by a reduction of intrahepatic and/or portocollateral resistances--can be potentiated by propranolol, which lowers the portal-venous inflow.

The increase in slow wave sleep which followed administration of the 5-HT2 receptor antagonist, ritanserin, was not significantly different between a group of 12 recovered, drug free depressed patients and a group of 12 health matched controls. The results suggests that there is no underlying abnormality in the 5-HT2 receptor regulation of slow wave sleep in recovered depressives, and that abnormalities in this measure reported previously in such patients may have been caused by use of concomitant tricyclic antidepressant medication. The baseline sleep parameters did not differ between recovered depressives and controls with the exception of stage 1 sleep, which was increased in the patient group.