Buspirone in the treatment of alcohol dependence: a placebo-controlled trial.

A double-blind controlled study of the effects of buspirone on alcohol dependence and associated symptoms in ambulatory alcoholics showed a marked improvement in both treatment and control groups. However, significant differences in favor of the medication were observed in several psychopathological measures, but not in measures of alcohol consumption. Contrary to a majority of prior controlled trials of buspirone in alcoholics, subjects were not selected on the basis of comorbid generalized anxiety; rather, the study tested the hypothesis of a direct effect on craving and consumption, independent from an anxiolytic effect. This hypothesis was not confirmed.

Effects of neuroleptic reduction in schizophrenic outpatients receiving high doses.

This paper presents an open study which evaluated the clinical effects of a partial and progressive reduction in neuroleptic medication in 32 outpatients suffering from schizophrenia who were receiving high doses (equivalent of > or = 18 mg of oral haloperidol per day; EHL). After an observation period of twelve weeks, each subject's dose of neuroleptics was reduced by 50% at the rate of 10% every four weeks. Patients were receiving a mean of 62 mg per day EHL at the beginning of the study and 30 mg per day EHL at the completion of the study. After the reduction, the following was observed: 1. a significant but modest change in psychopathology: a decrease in negative symptoms and in the total score on Brief Psychiatric Rating Scale; and 2. a significant increase in tardive dyskinesia symptoms. Six subjects relapsed but five of them recovered without increasing their reduced medication. Results of this study are discussed in the context of trying to find a minimal maintenance dose in the treatment of schizophrenia. The relative paucity of change despite a large reduction in medication argues for reevaluation of dosage in patients on high or very high doses of neuroleptics. The results suggest that many patients taking high doses could be maintained on significantly lower doses of neuroleptics. With gradual reduction of medication it would seem that many patients who are receiving a high dose of neuroleptic can achieve a lower dose than their current maintenance level.

Study of the clinical utility of radioreceptor assay in outpatients with schizophrenia receiving high doses of neuroleptics.

A radioreceptor assay (RRA) was used to determine the neuroleptic plasma levels of 32 outpatients with schizophrenia receiving a high dose of neuroleptics (the equivalent of 18 mg or more of oral haloperidol per day) and undergoing a 50% partial and progressive reduction (ten percent each month for five months) in their medication. Plasma levels of neuroleptics were measured three times: before (T1) and immediately after the 50% reduction (T2) and five months later (T3). A linear correlation was observed between neuroleptic plasma levels obtained by RRA and the neuroleptic doses prescribed at T1 and T3. Furthermore, neuroleptic plasma levels were significantly lower at T3 than at T1. Concurrent evaluations of psychopathology were done using the Brief Psychiatric Rating Scale, and the results indicated that no correlation exists between neuroleptic plasma levels and the total rating scale scores at T1 but a significant correlation was observed at T3.

Atypical neuroleptic-like behavioral effects of neurotensin.

To better characterize the neuroleptic-like properties of neurotensin, the dose-related effects of the peptide on the following behavioral phenomena were examined: a) the yawning-penile erection syndrome induced by small doses of the dopamine agonists apomorphine and N-propylnorapomorphine (NPA); b) yawning produced by the anticholinesterase physostigmine, and c) stereotyped climbing and sniffing produced by a larger dose of apomorphine. Several doses of the peptide were injected intraventricularly 30 min prior to drug administration. Results indicate that neurotensin markedly decreased yawning and penile erections produced by both apomorphine and NPA. These effects were seen with relatively small doses (0.9-3.75 micrograms). Neurotensin also potently decreased physostigmine-induced yawning with the initial inhibitory effect seen with 50 ng of the peptide. Apomorphine-induced climbing was significantly attenuated with 30.0 and 60.0 micrograms neurotensin, whereas stereotyped sniffing was unaffected, even by doses as large as 120.0 micrograms. These findings suggest that neurotensin might antagonize dopamine autoreceptors and indicate that the peptide possess central anticholinergic activity. Furthermore, these results lend support to the hypothesis that neurotensin's profile of central actions resemble that of atypical neuroleptics.

Neurotensin selectively antagonizes apomorphine-induced stereotyped climbing.

In order to better characterize the neuroleptic properties of neurotensin, the dose-related effects of the peptide on stereotyped climbing, sniffing and licking induced by 0.6 mg/kg apomorphine were examined. The following doses of the peptide were injected intraventricularly 30 min prior to apomorphine administration: 0.9, 3.75, 30.0 and 60 micrograms. Results indicate that, whereas oro-facial stereotypies remained unaffected by the peptide, stereotyped climbing was significantly decreased with the two largest doses of neurotensin. These findings indicate that the profile of neurotensin's neurobehavioral effects is more akin to that of atypical than typical neuroleptics.

Effects of neurotensin on regional brain concentrations of dopamine, serotonin and their main metabolites.

The effects of neurotensin, 7.5 or 30 micrograms, on concentrations of DA, DOPAC, (HVA), serotonin 5-HT and 5-HIAA were measured in 8 regions of the rat brain either 5 or 30 min following intracerebroventricular administration. Regions examined include the frontal cortex, striatum, nucleus accumbens, amygdala, septum, hypothalamus, ventral tegmentum and substantia nigra. Results indicate that both doses of neurotensin significantly elevated concentrations of dopamine in the striatum and amygdala 5 min following injection. The effects of the peptide on DOPAC and HVA were more pervasive and enduring, with significant increases in metabolite levels occurring in both mesolimbic and nigrostriatal terminal regions. In order to assess effects on turnover of dopamine, the ratios of each metabolic to dopamine concentrations were examined. Results indicate that, while the DOPAC/DA ratio was elevated in many regions, the HVA/DA ratio was increased in all regions examined. The effects of neurotensin on serotoninergic parameters were less pervasive and more variable, with both increases and decreases in 5-HT and 5-HIAA concentrations being observed. The effects of the peptide on 5-HIAA/5-HT were limited to the nucleus accumbens, where this ratio was increased, and the ventral tegmentum, where 5-HIAA/5-HT was decreased. These findings reveal that the effects of the neurotensin on dopaminergic transmission are more widespread than previously reported in that all major dopamine pathways are affected by the peptide. Also, the observed changes in the ratios of both DOPAC and HVA to DA suggest that neurotensin enhances the turnover of this transmitter.

[Who are the patients treated in an outpatient clinic with high dosage neuroleptics?]. / Qui sont les patients traités en clinique externe avec des doses élevées de neuroleptiques?

The use of high doses of neuroleptics (NL) in treatment of chronic psychosis is a controversial subject in the literature. In this context, it is surprising to note the lack of objective data about the prevalence and the consequences concerning this mode of prescription when treating people suffering from severe mental disorders. This study describes the clientele exposed to high doses of NL from an outpatient clinic of a psychiatric hospital. The equivalent of 18 mg or more of haloperidol per day was used as the high dose criterion. Overall, we observed the use of NL in all diagnostic categories and the frequent use of polypharmacy in patients treated with NL. Among the 435 patients receiving NL, 26.4% had high dose prescriptions (two men for every woman). Most of these high dose NL subjects had a diagnosis of schizophrenic disorder (87.9%). Fifty-one of them had been receiving high doses for six months or more and 39 of them agreed to meet our research team. The mean age of these subjects was 37.2 years and the mean dose was 63.5 mg haloperidol equivalent/day. Thirty-five subjects were diagnosed as chronic schizophrenic disorder and four as schizo-affective disorder. Nineteen patients had tardive dyskinesia. In two out of three cases the high dose prescription began during hospitalization and the main reason was presence of severe psychotic symptoms. Significant positive correlations were found between parkinsonian symptoms and negative symptoms of schizophrenia as well as psychosocial dysfunctions on 39 subjects. These findings support the hypothesis that the use of high doses of NL contribute to the negative symptoms and the psychosocial dysfunctions. The implications of these findings relating to assessment and treatment of schizophrenic outpatients are discussed.

The effects of neurotensin and [D-Tyr11]-NT on the hyperactivity induced by intra-accumbens administration of a potent dopamine receptor agonist.

The effects of neurotensin on the strong and persistent hyperactivity induced in rats by intra-accumbens administration of ADTN, a potent dopamine agonist, were examined. Neurotensin was administered intraventricularly as well as bilaterally into the accumbens. With both routes of administration neurotensin significantly decreased the hyperactivity produced by ADTN. However, important differences in doses required to produce this effect were noted between the two routes of administration. Whereas intraventricular injection of doses as small as 0.05 micrograms neurotensin was sufficient to reduce hyperactivity, bilateral intra-accumbens administration of at least 1.8 micrograms was required to replicate the effect. ADTN induced hyperactivity was also significantly decreased by intraventricular and intra-accumbens injections of the structural analog [D-Tyr11]-NT. In both routes of administration, the inhibitory action of the analog was more persistent than that observed with neurotensin. As was the case for neurotensin, intraventricular administration of [D-Tyr11]-NT was more potent than intra-accumbens injections. Finally, the results of a preliminary experiment indicate that neurotensin injected intraventricularly can also decrease hyperactivity elicited by intra-accumbens administration of dibutyryl cyclic AMP. Taken together, the results of the present study demonstrate that neurotensin can affect hyperactivity elicited by a strong and persistent activation of mesolimbic dopamine receptors or by stimulation of events beyond these receptors. The observed greater efficacy of intraventricularly administered neurotensin in decreasing ADTN induced hyperactivity suggests an action of the peptide on regions distant from the accumbens, probably on efferent outputs of mesolimbic stimulation.

Relationships between structure and duration of neurotensin's central action: emergence of long acting analogs.

Relationships between structure and duration of neurotensin's central action were examined. Included in the study were analogs containing amino acid substitutions at purported enzymatic cleavage sites of neurotensin: the arg8-arg9, the Pro10-Tyr11, and the Tyr11-Ile12 peptide bonds. Peptides were administered in rats via the cerebro-ventricular route and the ensuing hypothermia was monitored repeatedly until the effect dissipated. Results indicate that substitutions of the Tyr11 residue of the neurotensin molecule with either Dopa, Trp, D-Trp, or D-Tyr yielded analogs displaying markedly increased durations of action. Substitutions at other sites did not alter the time course of neurotensin's hypothermic effect. The longest acting analog was [Dopa11]-NT. At a dose of 7.5 micrograms the hypothermia induced by this analog persisted for 660 min while the effect of a same dose of neurotensin endured for only 90 min after injection. No clear correlation was found between the relative potency of analogs and their duration of action. Taken together, the results confirm the predominant role of Tyr11 in the inactivation of neurotensin by the brain, but do not support the hypothesis that relative potencies of structural analogs are solely dependent on differing susceptibilities to enzymatic degradation.