Lower angiotensin I converting enzyme activity in melancholic subjects: a pilot study.
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Adult↗
Biomedical subjects
H Y Meltzer
Publications and source records attributed to H Y Meltzer.
Serotonergic measures in suicide brain: the concentration of 5-HIAA, HVA, and tryptophan in frontal cortex of suicide victims.
Concentrations of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and tryptophan (TRP) were determined in the frontal cortex of individuals who died by suicide, homicide, accident, or the result of physical diseases. Females had significantly higher tryptophan concentrations than males. There was a significant correlation HVA and the interval between death to refrigeration of the body. Mean HVA levels were higher from noon to 5 PM. Suicide and homicide victims had significantly higher cortical HVA concentrations than those who died of physical disease but not accident victims. This was not accounted for by gender, age, postmortem interval from death to refrigeration of the body or to autopsy, specimen storage time, or drug effects. The ratio of HVA/5-HIAA was also significantly higher in suicides compared with those who died of physical disease. No differences in cortical 5-HIAA or tryptophan concentrations between the four groups were found. There were no differences in the levels of the three substances in violent and nonviolent suicides. There were no significant correlations between 5-HIAA, HVA and TRP concentrations in all subjects or any of the four subgroups. The implications of these findings for the role of serotonin and dopamine in suicide and violence are discussed.
Accidents↗
The effect of chronic clozapine on basal dopamine release and apomorphine-induced DA release in the striatum and nucleus accumbens as measured by in vivo brain microdialysis.
Previous studies have produced conflicting results concerning the effect of chronic oral vs. parenteral (i.p.) clozapine administration on dopamine (DA) release and metabolism in the striatum and nucleus accumbens (n. accumbens) of freely moving rats using in vivo microdialysis. In this study, parenteral chronic clozapine (20 mg/kg/day for 21 days, i.p.) had no effect on basal DA release and metabolism in either region. Chronic treatment with parenteral clozapine also did not reverse the decrease in DA release and metabolism in striatum and n. accumbens produced by apomorphine (100 micrograms/kg, s.c.). These results differ significantly from a previous report following i.p. clozapine and confirm the results previously reported with oral clozapine.
3,4-Dihydroxyphenylacetic Acid↗
Effect of amperozide on rat cortical 5-HT2 and striatal and limbic dopamine D2 receptor occupancy: implications for antipsychotic action.
Amperozide (FG 5606, N-ethyl-4-[4',4'-bis(p-fluorophenyl)butyl]-1-piperazine-carboxamide) is an atypical antipsychotic drug which has relatively weak in vitro affinity for striatal dopamine2 (D2) receptors and strong affinity for cortical 5-HT2 receptors. The in vivo affinity for 5-HT2 binding sites in rat cortex was 1.1 mg/kg. In striatum or olfactory tubercle, doses of amperozide up to 40 mg/kg did not displace radioligand binding to D2 receptors. Amperozide, haloperidol and ritanserin had similar in vivo potency in blocking the 5-HT2 binding site, but only haloperidol displaced D2 receptor binding. Based on the clinically effective dose of amperozide (0.14-0.28 mg/kg per day), it is suggested that the antipsychotic effect of amperozide is related, in part, to its in vivo interaction with the 5-HT2 receptor and that amperozide cannot be expected to exert its antipsychotic action by blockade of D2 receptors in the striatum or limbic regions.
Animals↗
The effect of chronic atypical antipsychotic drugs and haloperidol on amphetamine-induced dopamine release in vivo.
The effect of chronic administration of antipsychotic drugs (21 days in drinking water followed by 3 days drug washout) on the D-amphetamine (1.0 mg/kg, s.c.)-induced increase in dopamine (DA) release in the striatum and the nucleus accumbens of awake, freely-moving rats was investigated with microdialysis. Chronic administration of haloperidol, a typical antipsychotic, (0.5 mg/kg/day), decreased basal extracellular DA release in the striatum and the nucleus accumbens but did not affect D-amphetamine-induced DA release in either region. In marked contrast, chronic administration of three atypical antipsychotic drugs: amperozide (2 mg/kg/day), clozapine (10 mg/kg/day) and melperone (2 mg/kg/day) increased basal extracellular DA and enhanced D-amphetamine-induced DA release in the striatum. In the nucleus accumbens, basal extracellular DA was decreased by chronic amperozide, unchanged by chronic clozapine and increased by chronic melperone. Most significantly, D-amphetamine-induced DA release was inhibited by chronic amperozide or clozapine, but unaffected by chronic melperone in this region. These results suggest that atypical antipsychotic drugs can alter DA release in a region specific manner. In particular, attenuation of amphetamine-like stimulation of DA release with reduced basal DA release in the nucleus accumbens could contribute to the antipsychotic action of amperozide which has a very weak affinity for D2 DA receptors.
3,4-Dihydroxyphenylacetic Acid↗
In vivo occupancy of dopamine receptors by antipsychotic drugs.
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Animals↗
Effect of typical antipsychotic medications and clozapine on smooth pursuit performance in patients with schizophrenia.
The effect of typical neuroleptic drugs or clozapine on smooth pursuit eye movements was tested in 13 patients with schizophrenia or schizoaffective disorder with a repeated measures design. Nineteen normal control subjects were also studied. Compared with controls, patients in the unmedicated state had low smooth pursuit gain, had a higher rate of corrective catch-up saccades, and tended to spend less time engaged in the tracking task. The patients did not significantly differ from controls on catch-up saccade amplitude, square wave jerk rate, or anticipatory saccade rate. Medication with clozapine, but not typical neuroleptics, was associated with an increase in median catch-up saccade amplitude. Number of days on clozapine and clozapine dose both correlated significantly with a worsening of oculomotor performance. No effect of medication with typical neuroleptics was found, although there was some evidence suggesting that such an affect may occur after more prolonged treatment.
Adult↗
Treatment of the neuroleptic-nonresponsive schizophrenic patient.
The treatment and management of neuroleptic-resistant schizophrenic patients, who comprise 5 to 25 percent of all patients with that diagnosis, are major problems for psychiatry. In addition, another large group of schizophrenic patients, perhaps 5 to 20 percent, are intolerant of therapeutic dosages of neuroleptic drugs because of extrapyramidal symptoms, including akathisia, parkinsonism, and tardive dyskinesia. Because about 60 percent of neuroleptic-resistant schizophrenic patients respond to clozapine and a large percentage of neuroleptic-intolerant patients are able to tolerate clozapine, it should be considered the treatment of choice for such patients until other therapies are proven to be superior. A trial of clozapine alone should usually be continued for up to 6 months before it is terminated or supplemental agents are tried. Plasma levels of clozapine may be useful to guide dosage. The major side effects of clozapine are granulocytopenia or agranulocytosis (1%-2%) and a dose-related increase in the incidence of generalized seizures. Psychosocial treatments such as education of the patient and the family about the nature of the illness, rehabilitation programs, social skills training, and assistance in housing are generally needed to obtain optimal benefit from clozapine, as with other somatic therapies. If clozapine is unavailable, unacceptable, or not tolerated, a variety of approaches may be employed to supplement typical antipsychotic drugs for patients who do not respond adequately to these agents alone. These include lithium; electroconvulsive therapy; carbamazepine or valproic acid; benzodiazepines; antidepressant drugs; reserpine; L-dopa and amphetamine; opioid drugs; calcium channel blockers; and miscellaneous other pharmacologic approaches. The evidence for the efficacy of these ancillary somatic therapies in treatment-resistant patients is relatively weak. Polypharmacy should be tried only for discrete periods and with clear goals. If these are not achieved, supplemental medications should be discontinued. Psychosurgery is not a recommended alternative at this time.
Antipsychotic Agents↗
Clinical services research.
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Activities of Daily Living↗
Platelet imipramine binding in depressed children and adolescents.
Kinetic constants of platelet imipramine binding were determined in youths with major depression, and a contrast group. Subjects actively depressed (N = 10) had significantly fewer imipramine binding sites (Bmax) (877 +/- 148 fmol/mg protein) than recovering depressives (N = 12) (1220 +/- 428 fmol/mg protein) and contrasts (N = 10) (1270 +/- 230 fmol/mg protein). Affinity constants (Kd) (1.14 +/- 0.36 nM, 0.97 +/- 0.31 nM, and 1.17 +/- 0.39 nM, respectively) were similar among the groups. Actively depressed males but not females had fewer imipramine binding sites than both their sex-matched comparison groups. Although actively depressed females' Bmax was significantly lower than recovering depressed and nondepressed males, neither age, Tannner stage, nor circannual rhythms influenced Bmax, but suicidality may be associated with low Bmax. A decrease in Bmax may be a state-specific marker of major depression in boys or associated with a depressive disorder with a suicidal history.
Adolescent↗
Amperozide, a novel antipsychotic drug, inhibits the ability of d-amphetamine to increase dopamine release in vivo in rat striatum and nucleus accumbens.
The in vivo effects of amperozide, a novel atypical antipsychotic drug, on the release of dopamine (DA) and the output of its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), were investigated in the striatum and the nucleus accumbens of awake, freely moving rats using microdialysis. Amperozide (2-10 mg/kg, s.c.) significantly increased extracellular levels of DA in both the striatum and nucleus accumbens in a dose-dependent manner. It had a similar but lesser effect on extracellular DOPAC levels in both regions. d-Amphetamine (2 mg/kg, s.c.) alone produced a very large (43-fold) increase in DA release, together with a 70% decrease in DOPAC levels in both the striatum and the nucleus accumbens. Amperozide (1-5 mg/kg, s.c.) 30 min before d-amphetamine (2 mg/kg) dose-dependently attenuated d-amphetamine-induced DA release but had no effect on the d-amphetamine-induced decrease in extracellular DOPAC levels in both regions. The effect of amperozide on d-amphetamine-induced DA release in the nucleus accumbens may explain the inhibitory effect of amperozide on amphetamine-induced locomotor activity. However, the failure of amperozide to block amphetamine-induced stereotypy, despite marked inhibition of striatal DA release, suggests the need to reexamine the importance of striatal DA for amphetamine-induced stereotypy.
3,4-Dihydroxyphenylacetic Acid↗
Binding of typical and atypical antipsychotic agents to transiently expressed 5-HT1C receptors.
We determined the affinities of clozapine and 21 other typical and atypical antipsychotic agents for the cloned 5-hydroxytryptamine-1C (5-HT1C) receptor. For these studies, 5-HT1C receptors were transiently expressed in COS-7 cells using the vector pSVK3-5HT1C. We discovered that clozapine and several other putative typical and atypical antipsychotic agents (loxapine greater than tiosperone greater than SCH23390 greater than fluperlapine greater than rilapine greater than chlorpromazine) had relatively high affinities (7-30 nM) for the cloned 5-HT1C receptor. Other antipsychotic agents (risperidone greater than tenilapine greater than mesoridazine greater than thioridazine greater than cis-fluphenthixol) had intermediate affinities (30-100 nM), whereas many other antipsychotics (fluphenazine greater than spiperone greater than amperozide greater than melperone greater than thiothixene greater than haloperidol, metoclopramide, pimozide, domperidone, sulpiride) had low affinities (greater than 500 nM) for the cloned 5-HT1C receptor. The results indicate that although several putative atypical antipsychotic agents have high affinities for the cloned rat 5-HT1C receptor, the spectrum of drug binding does not correlate with the atypical nature of these compounds.
Antipsychotic Agents↗
The importance of serotonin-dopamine interactions in the action of clozapine.
Clozapine has an affinity for the dopamine (DA) D2 receptor which is relatively weak but is in line with its average clinical dose when compared with typical neuroleptic drugs. A few atypical antipsychotic drugs may have high absolute affinities for the D2 receptor, but most are weak D2 blockers. The atypical antipsychotic drugs also differ from the typical antipsychotic drugs by a relatively high affinity for the serotonin (5-HT2) receptor. This is evident on both in vitro and in vivo binding to cortical 5-HT2 receptors. The atypical antipsychotics are best distinguished from the typical antipsychotics on the basis of the relationship between strong 5-HT2 and weak D2 affinities. High D1 receptor binding is not characteristic of the group of atypical drugs. A new group of putative atypical antipsychotic drugs with high affinities for 5-HT2 compared to D2 receptors is under study.
Antipsychotic Agents↗
The effect of the atypical antipsychotic drug, amperozide, on carrier-mediated striatal dopamine release measured in vivo.
The effect of the novel atypical antipsychotic drug, amperozide, on carrier-mediated dopamine efflux was studied using in vivo microdialysis in the striatum of awake-behaving rats. Amperozide was infused directly through the dialysis probe. This local infusion produced a concentration-dependent increase in striatal dopamine overflow. This increase was attenuated when a Ca(++)-free perfusion medium was used. Local infusion of amperozide blocked dopamine efflux after the systemic administration of amphetamine in a concentration-dependent manner. The antagonistic effect of amperozide (50 microM) on amphetamine-induced efflux of dopamine was not attenuated under Ca(++)-free conditions. Similar to its effects on amphetamine-induced dopamine efflux, amperozide (50 microM) attenuated the increase in dopamine overflow produced by ouabain (10 microM) but not veratridine (15 microM). The systemic coadministration of amperozide (10 mg/kg, i.p.) and haloperidol (2 mg/kg, i.p.) increased extracellular dopamine levels in an additive manner when compared to the increases observed after the administration of either drug alone. Overall, these data indicate that amperozide acts on the dopamine transporter to inhibit carrier-mediated release.
Animals↗
Dimensions of outcome with clozapine.
Various outcome measures following clozapine administration to neuroleptic-resistant schizophrenic patients are considered. The importance of a multidimensional perspective is emphasised. There was significant improvement in positive symptoms, some negative symptoms, quality of life, some types of cognitive function (e.g. semantic memory), extrapyramidal function, and tardive dyskinesia. Readmission to hospital, and family burden were markedly reduced, which achieved significant savings in the cost of treatment. Compliance with clozapine and weekly blood testing can be achieved in the majority of treatment-resistant cases. These benefits may occur independently of each other.
Adult↗
Behavioral rating scales for assessing phencyclidine-induced locomotor activity, stereotyped behavior and ataxia in rats.
Behavioral rating scales were developed for quantification of phencyclidine (PCP)-induced locomotor activity, stereotyped behavior and ataxia in rats. The dose-response relationship for PCP-induced locomotor activity was found to be an inverted U-shaped function over the first 25 min after injection while over the last 30 min of the experiment the function was highly linear. A linear dose-response relationship was found for ratings of stereotyped behavior and ataxia throughout the 90 min period of observation. The ratings of these two behaviors were found to be closely parallel. The effects of PCP on locomotor activity were found to be greatest during those intervals when stereotyped behavior and ataxia were at moderate levels. Ratings of locomotor activity may be confounded by ataxia when PCP is administered alone or in combination with other drugs.
Animals↗
Distribution of type A and type B monoamine oxidase activities in rat and chicken skeletal muscle and nerves.
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Animals↗
Repeated administration of 5-methoxy-N,N-dimethyltryptamine to male rats potentiates stimulation of prolactin secretion by serotonin agonists.
Repeated administration of 5-methoxy-N,N-dimethyltryptamine (5MeODMT, 5 mg/kg, a serotonin agonist, every 3 h for a total of 4 injections) potentiated its prolactin (PRL)-releasing effect and that of two other serotonin agonists, quipazine and N,N-dimethyltryptamine. This pretreatment schedule had no effect on PRL response to anti-dopaminergic drugs. The onset of enhanced PRL response to serotonin agonists was gradual and appears to be due to sensitization of the serotonergic mechanism involved in the regulation of PRL secretion. The possible mechanisms underlying this phenomenon are discussed.
Animals↗