clozapine and metylperon

Since the development of clozapine the investigation of atypical neuroleptic compounds has become increasingly relevant. Compared with classic neuroleptics they are distinguished by either fewer or absent (clozapine) extrapyramidal side effects, some of them also by lower increases of serum prolactin concentrations. Pharmacologically they are a group of heterogeneous substances. At the level of transmitter systems a high 5HT2/D2-ratio is regarded as the best criterion to distinguish between atypical and classic neuroleptics. Further differences involve: the preferred effects of atypical neuroleptics on mesolimbic D2 receptors compared to striatal dopaminergic neurotransmission; a higher potency of some atypical neuroleptics to antagonize D1-receptors; the increase of serum corticosterone concentrations by some of the atypical neuroleptics.

Topics: Animals; Antipsychotic Agents; Brain; Butyrophenones; Clinical Trials as Topic; Clozapine; Humans; Psychotic Disorders; Receptors, Dopamine D1; Receptors, Dopamine D2; Receptors, Serotonin

To evaluate the effect of melperone, a butyrophenone with atypical antipsychotic properties, on plasma prolactin (PRL) concentrations compared with clozapine and typical neuroleptics.. Analysis of pre- and post-treatment PRL levels collected prospectively per protocol in a non-randomized study of 26 melperone-, 76 clozapine-, and 66 neuroleptic-treated patients with schizophrenia or schizoaffective disorder. Cross-sectional analysis of a larger sample of patients with PRL data was also performed.. For males, post-treatment PRL levels were significantly higher in the typical neuroleptic group compared with the melperone (p = 0.0001) and clozapine (p = 0.0001) groups, with no significant difference between clozapine and melperone. For females, post-treatment PRL levels were significantly higher in the melperone group as compared to the clozapine group (p = 0.004). There were too few typical neuroleptic-treated females to permit analysis of this sample. However, the cross-sectional analysis of PRL data confirmed the results for melperone- and clozapine-treated females, and showed higher PRL levels in typical neuroleptic-treated females as compared with those who received melperone and clozapine.. Melperone did not significantly increase PRL levels in male patients. However, melperone and typical neuroleptics caused increase in PRL levels in females. Further study of melperone's effects on PRL concentration is warranted.

Topics: Adult; Antipsychotic Agents; Butyrophenones; Clozapine; Female; Humans; Male; Mental Disorders; Prolactin; Sex Factors

To evaluate the practical utility of off-licence prescribing and clinical outcomes of treatment with atypical antipsychotic Melperone.. Prospective data collection on patient's clinical characteristics and outcomes.. 17 patients with a diagnosis of refractory schizophrenia were identified as suitable for off-license prescribing of Melperone and commenced treatment (13 were previously treated with Clozapine). Seven of those currently remain on Melperone (41%), and for six patents, the BPRS symptom scores reduced significantly over time (24-61%) additionally patients displayed improvements of their quality of life. Six patients were discontinued due to noncompliance and/or side effects. Melperone was ineffective in the other four patients.. The example of a small group of patients responding well to a comparably safe and inexpensive atypical antipsychotic with favourable side effect profile should encourage clinicians to use this tool as third-line treatment and to conduct more systematic clinical research.

Topics: Adult; Antipsychotic Agents; Butyrophenones; Clozapine; Female; Follow-Up Studies; Humans; Male; Medical Audit; Middle Aged; Off-Label Use; Prospective Studies; Quality of Life; Schizophrenia; Severity of Illness Index; Treatment Outcome; Young Adult

Melperone is an atypical antipsychotic drug that has been reported to be effective in treatment-resistant schizophrenia and L-DOPA psychosis. There are limited data concerning its effect on weight or body mass index (BMI). Weight and BMI were retrospectively compared in patients with schizophrenia treated with melperone (n=34), clozapine (n=225), or typical neuroleptics (n=74) for up to 3 months. Clozapine resulted in significant increases in weight and BMI from baseline to 6 weeks and 3 months. Neither melperone nor typical neuroleptics resulted in significant weight gain at either time point. Melperone did not result in significant increases in BMI. Weight and BMI were significantly lower with melperone compared with clozapine, but similar to typical neuroleptics. The proportion of melperone patients who experienced a >or=7% weight increase was lower than that in patients treated with clozapine and similar to that in patients treated with typical neuroleptics. Percent change in weight and BMI predicted improvement in BPRS total scores at 3 months in the clozapine group, but not in the melperone or typical neuroleptic groups. Because of the relationship between BMI and cardiovascular risk, melperone deserves further study as both a first line treatment and as an alternative to clozapine in refractory schizophrenia.

Topics: Adult; Analysis of Variance; Antipsychotic Agents; Body Mass Index; Body Weight; Butyrophenones; Clozapine; Female; Humans; Male; Schizophrenia; Time Factors

A model of the dopamine D2 receptor was used to study the receptor interactions of dopamine, the typical antipsychotics haloperidol and loxapine, and the atypical antipsychotics clozapine and melperone. The atypical antipsychotics interacted with the halogen atom of the ring system in the direction of the transmembrane helices (TMHs) 2, 3 and 7, while the typical had the corresponding halogen atom in the direction of TMH5. Molecular dynamics simulations indicated that the average helical displacement upon binding increased in the order: typical < atypical < dopamine. Upon binding, the atypical induced larger displacements into TMH5 than did the typical. The typical had stronger non-bonded interactions with the receptor than had the atypical, which is in agreement with the experimental observation that the atypical antipsychotic drugs dissociate faster from the receptor than the typical antipsychotic drugs.

Topics: Antipsychotic Agents; Binding Sites; Butyrophenones; Clozapine; Drug Interactions; Halogens; Humans; Ligands; Loxapine; Molecular Structure; Receptors, Dopamine D2

Clozapine (CLZ), an atypical antipsychotic drug (APD), produces minimal extrapyramidal side effects (EPS) and has significant advantages for treating both positive and negative symptoms in schizophrenic patients. CLZ has been established as a discriminative cue in the drug discrimination paradigm and in generalization tests the CLZ cue is more selective for atypical, rather than typical, APDs. However, greater selectivity for atypical antipsychotics has been demonstrated with a lower (1.25 mg/kg) CLZ training dose in rats [Psychopharmacology, 149 (2000) 189], rather than the traditional, higher training dose (5.0 mg/kg). It is therefore of interest to evaluate the properties mediating the 1.25 mg/kg CLZ discriminative cue. In the present study, rats were trained to discriminate either 1.25 mg/kg (N=7) or 5.0 mg/kg (N=7) CLZ from vehicle in a two-lever drug discrimination task. The typical antipsychotic haloperidol (0.1-0.4 mg/kg) did not substitute for either CLZ cue, whereas the atypical antipsychotic melperone (0.37-3.0 mg/kg) provided full substitution in both groups (>80% CLZ-appropriate responding). The 5-HT(1A) receptor agonist (+)-8-OH-DPAT (0.04-0.16 mg/kg), and the selective 5-HT(2A) receptor antagonist M100907 (0.03-1.0 mg/kg) did not produce substitution in either group. (+)-8-OH-DPAT combined with haloperidol (0.05 mg/kg) engendered only partial substitution (>60% CLZ-appropriate responding) for both CLZ cues, and M100907 combined with haloperidol (0.05 and 0.1 mg/kg doses) failed to provide substitution in either group. Trihexyphenidyl (0.18-6.0 mg/kg), a muscarinic M(1)-preferring receptor antagonist, engendered full substitution for the 1.25 mg/kg CLZ cue, but only partial substitution for the 5.0 mg/kg CLZ cue. These results provide evidence that antagonism at the muscarinic M(1) receptor is sufficient to provide 1.25 mg/kg CLZ-like discriminative stimulus effects.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Antipsychotic Agents; Butyrophenones; Clozapine; Discrimination, Psychological; Dopamine; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Fluorobenzenes; Generalization, Stimulus; Haloperidol; Male; Muscarinic Antagonists; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Trihexyphenidyl

Preferential increases in both cortical dopamine (DA) and acetylcholine (ACh) release have been proposed to distinguish the atypical antipsychotic drugs (APDs) clozapine, olanzapine, risperidone and ziprasidone from typical APDs such as haloperidol. Although only clozapine and ziprasidone are directly acting 5-HT(1A) agonists, WAY100635, a selective 5-HT(1A) antagonist, partially attenuates these atypical APD-induced increases in cortical DA release that may be due to combined 5-HT(2A) and D(2) blockade. However, WAY100635 does not attenuate clozapine-induced cortical ACh release. The present study determined whether quetiapine, iloperidone and melperone, 5-HT(2A)/D(2) antagonist atypical APDs, also increase cortical DA and ACh release, and whether these effects are related to 5-HT(1A) agonism. Quetiapine (30 mg/kg), iloperidone (1-10 mg/kg), and melperone (3-10 mg/kg) increased DA and ACh release in the medial prefrontal cortex (mPFC). Iloperidone (10 mg/kg) and melperone (10 mg/kg), but not quetiapine (30 mg/kg), produced an equivalent or a smaller increase in DA release in the nucleus accumbens (NAC), respectively, compared to the mPFC, whereas none of them increased ACh release in the NAC. WAY100635 (0.2 mg/kg), which alone did not affect DA or ACh release, partially attenuated quetiapine (30 mg/kg)-, iloperidone (10 mg/kg)- and melperone (10 mg/kg)-induced DA release in the mPFC. WAY100635 also partially attenuated quetiapine (30 mg/kg)-induced ACh release in the mPFC, but not that induced by iloperidone (10 mg/kg) or melperone (10 mg/kg). These results indicate that quetiapine, iloperidone and melperone preferentially increase DA release in the mPFC, compared to the NAC via a 5-HT(1A)-related mechanism. However, 5-HT(1A) agonism may be important only for quetiapine-induced ACh release.

Topics: Acetylcholine; Animals; Antipsychotic Agents; Butyrophenones; Clozapine; Dibenzothiazepines; Dopamine; Haloperidol; Isoxazoles; Male; Microdialysis; Nucleus Accumbens; Piperidines; Prefrontal Cortex; Quetiapine Fumarate; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT1

The dopamine D4 receptor, which is considered a close variant of the dopamine D2 receptor, has recently been cloned. Receptor binding studies demonstrated that clozapine, which is an effective antipsychotic agent but atypical in that it lacks the usual side effects of other antipsychotic agents, has high selectivity for the dopamine D4 receptor versus the dopamine D2 receptor. Comparative binding affinity studies have been carried out for a number of interesting dopaminergic agents using membranes prepared from cloned dopamine D2 and D4 receptor containing cells. It was found that clozapine is selective for the dopamine D4 vs. the D2 receptor by a factor of 2.8. Other compounds with dopamine D4 receptor selectivity were (+)-apomorphine (8.7), (+)-N-propyl-norapomorphine (NPA) (2.4) and melperone (1.3). Compounds with considerable selectivity for the dopamine D2 receptor were haloperidol (0.31), chlorpromazine (0.084), trifluoperazine (0.034) and raclopride (0.001). Overall, the results with the antipsychotic agents tested, support the concept that dopamine D4 receptor selectivity may confer clozapine-like antipsychotic efficacy and furthermore that dopamine D2 receptor selectivity may confer side effect liability (extrapyramidal side effects and tardive dyskinesia).

Topics: Animals; Apomorphine; Butyrophenones; Cell Line; Chlorpromazine; Clozapine; Dopamine Agents; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Haloperidol; Raclopride; Radioligand Assay; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Dopamine D4; Salicylamides; Trifluoperazine

Amperozide, a new putatively antipsychotic compound, has been evaluated for its effect on conditioned avoidance response and food-reinforced lever-pressing. Given alone, amperozide was almost equipotent to clozapine, but less potent than haloperidol in both test models. It was found that there was a statistically significant synergism, in these two models, between amperozide and classical neuroleptics. Since amperozide is inactive in behavioural tests reflecting striatal dopaminergic mechanisms, the synergistic effect could be of great therapeutic value in the treatment of psychotic disorders.

Topics: alpha-Methyltyrosine; Animals; Antipsychotic Agents; Avoidance Learning; Behavior, Animal; Butyrophenones; Chlorpromazine; Clozapine; Conditioning, Operant; Drug Synergism; Female; Food; Haloperidol; Male; Methyltyrosines; Piperazines; Psychotropic Drugs; Rats; Rats, Inbred Strains; Reinforcement Schedule

The effect of acute treatment with seven atypical antipsychotic drugs and four typical antipsychotic drugs on serotonin2 (5-HT2) receptor binding sites in rat cerebral cortex was studied. Among the atypical antipsychotic drugs examined, clozapine, fluperlapine, RMI-81582 and setoperone decreased the density of 5-HT2 receptors, but ticspirone, amperozide and melperone did not. None of the drugs affected the Kd value. Among the typical antipsychotic drugs, loxapine decreased Bmax and increased the Kd of 5-HT2 receptor binding sites, whereas chlorpromazine and cis-flupenthixol had no effect. Clothiapine, a typical antipsychotic drug of the same chemical class as clozapine, decreased Bmax without increasing Kd. The downregulation of 5-HT2 receptor binding sites following a single injection of clozapine, 20 mg/kg, remained almost unchanged during the first 72 hrs and was still significantly decreased for up to 120 hrs. There was no relationship between the affinity for the downregulation of rat cortical 5-HT2 receptor binding site and 5-HT2 receptor density. Coadministration of the D1 dopamine agonist, SKF-38393, did not affect the clozapine-induced downregulation. It is suggested that rapid and prolonged downregulation of 5-HT2 receptor sites is characteristic of some but not all atypical antipsychotic drugs and is not specific to atypical antipsychotic drugs. Dibenzo-epines (clozapine, loxapine, amoxapine, chlothiapine) consistently downregulate 5-HT2 receptors in frontal cortex after acute treatment.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Antipsychotic Agents; Butyrophenones; Cerebral Cortex; Chlorpromazine; Clozapine; Dibenzazepines; Dibenzothiazepines; Down-Regulation; Flupenthixol; Kinetics; Loxapine; Male; Pyrimidinones; Rats; Rats, Inbred Strains; Receptors, Serotonin; Spiro Compounds; Time Factors

The effects of atypical neuroleptics within the neuroendocrine axis of rodents can be distinguished from those of typical neuroleptics by the production of: 1) a shortlived increase in serum PRL concentrations, 2) an acute increase in the activity of TIDA neurons, and 3) a marked increase in serum corticosterone concentrations. It is of interest to speculate that the pharmacological properties of atypical neuroleptics which mediate the unique neuroendocrine responses are of relevance to an understanding of the mechanisms which underlie the clinical profile of these antipsychotic agents.

Topics: Animals; Antipsychotic Agents; Arcuate Nucleus of Hypothalamus; Butyrophenones; Clozapine; Corticosterone; Dibenzazepines; Dihydroxyphenylalanine; Dose-Response Relationship, Drug; Male; Median Eminence; Neurons; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine

The ability of atypical and typical antipsychotics to antagonize serotonin (5-HT) receptor-mediated temperature and neuroendocrine responses was tested in rats. Clozapine, melperone and setoperone, three atypical neuroleptics, blocked in a dose-dependent manner, the hyperthermic response to the 5-HT agonist, MK-212, whereas chlorpromazine and haloperidol were ineffective. The hypothermic response to the 5-HT1A agonist, 8-OH-DPAT, was unaltered by any of the atypical neuroleptics tested. Similarly, MK-212-induced corticosterone secretion was blocked in a dose-related manner by clozapine, melperone and setoperone but was relatively unaffected by either haloperidol or chlorpromazine. The increase in corticosterone secretion observed following 8-OH-DPAT administration was not attenuated by pretreatment with the atypical or typical antipsychotics tested. These data indicate that atypical neuroleptics are effective 5-HT2 but not 5-HT1A antagonists in vivo. Conversely, the typical neuroleptics, haloperidol and chlorpromazine do not block the 5-HT receptors involved in activation of the hypothalamic-pituitary-adrenal axis or thermoregulation.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Antipsychotic Agents; Body Temperature; Butyrophenones; Chlorpromazine; Clozapine; Corticosterone; Haloperidol; Male; Neurosecretory Systems; Pyrazines; Pyrimidinones; Rats; Rats, Inbred Strains; Receptors, Serotonin; Serotonin Antagonists; Tetrahydronaphthalenes