piperidines and zotepine

There have been concerns that antipsychotics increase the incidence of hyperglycemic progression. Many factors have been suggested to contribute to the risk of antipsychotic-induced hyperglycemic progression, including the type, daily dose, and number of antipsychotics; however, few studies have examined these relationships. This study aimed to examine the affect of antipsychotic treatment-associated factors on hyperglycemic progression, after adjustment for the affect of background factors suggested to be associated with hyperglycemic progression. This was a nationwide, multicenter, prospective cohort study examining the incidence of hyperglycemic progression during a 12 mo period following the initiation of newly prescribed antipsychotic medication. Demographic data, medication history, and blood test values were collected from 631 study participants with normal blood glucose levels at baseline for 12 mo. The primary endpoint (incidence of hyperglycemic progression) was defined as progression from normal to prediabetic or probable diabetic status, and was evaluated based on the Japanese monitoring guidance in patients with schizophrenia. To further examine the affect of antipsychotics on glucose metabolism over time, we examined changes in HbA1c levels 3, 6, and 12 mo after the initiation of treatment with each antipsychotic. We found that treatment with zotepine and clozapine was associated with a significantly high incidence of hyperglycemic progression. Furthermore, changes in HbA1c levels 6 mo after the initiation of zotepine treatment were significantly higher than those following blonanserin and haloperidol treatments. In contrast, there was no significant difference in the change in total cholesterol, triglycerides, HDL cholesterol, and BMI during the same period. Moreover, the "daily dose" and "number" of antipsychotics did not show an association with the incidence of hyperglycemic progression. However, in a post hoc analysis in which the antipsychotics were divided into two groups according to the strength of blockade of H

Topics: Adult; Antipsychotic Agents; Clozapine; Dibenzothiepins; Female; Haloperidol; Humans; Hyperglycemia; Incidence; Japan; Male; Middle Aged; Piperazines; Piperidines; Prospective Studies; Schizophrenia

To clarify clinical roles of sigma receptor binding affinity of neuroleptics, neck dystonia induced by microinjection of sigma receptor ligands and neuroleptics into rat red nucleus was investigated. DTG and (+)-3-PPP, putative sigma receptor agonists, induced neck dystonia in dose-dependent and reversible manner. Haloperidol and perphenazine induced dystonia in the same way as sigma receptor agonists, whereas zotepine and (-)-sulpiride did not. The rank order of potency in induction of dystonia and sigma receptor affinity of these compounds showed positive correlation. Although BMY-14802 has a high affinity for sigma receptors, it never produced dystonia by itself. On the other hand, combined injection of BMY-14802 with DTG attenuated DTG-induced dystonia. Therefore, it is suggested that typical neuroleptics such as haloperidol act agonistic and atypical neuroleptics such as BMY-14802 act antagonistic at rubral sigma receptors in the induction of neck dystonia.

Topics: Animals; Antipsychotic Agents; Dibenzothiepins; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dystonia; Guanidines; Haloperidol; Male; Microinjections; Nerve Tissue Proteins; Perphenazine; Piperidines; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, sigma; Red Nucleus; Sulpiride; Torticollis

The effect of the atypical neuroleptic zotepine (CAS 26615-21-4), in comparison with clozapine, risperidone and haloperidol, on the responsiveness of different 5-hydroxytryptamine (5-HT1) receptor subtypes to their agonists was examined in rats and mice. The above antipsychotics were investigated in the following behavioural tests: 8-OH-DPAT (8-hydroxy-dipropylaminotetralin)-induced behavioural syndrome in rats, mCPP (mchlorophenylpiperazine)-induced hypothermia in mice and mCPP-induced hypoactivity measured in the open field in rats. Zotepine, clozapine and haloperidol did not affect the behavioural syndrome induced by 8-OH-DPAT (the selective agonist of 5-HT1A, receptor), only risperidone (used in higher doses) attenuated the effect of 8-OH-DPAT. The mCPP-induced hypothermia in mice (a 5-HT1B effect) was affected by neither zotepine nor clozapine, risperidone and haloperidol, all of them used in low doses which did not influence per se the body temperature of mice. All the tested antipsychotics given at high doses induced hypothermia in control mice; at the same time, zotepine, clozapine and risperidone attenuated the hypothermic effect of mCPP. mCPP decreases the exploratory activity of rats, this effect being considered to be mediated by 5-HT1C receptors. The tested antipsychotics, used in low doses, influenced neither the exploratory activity nor the hypoactivity induced by mCPP. When used at higher doses, they induced hypoactivity in control rats; the hypoactivity after joint administration of zotepine, risperidone or haloperidol and mCPP was significantly greater than after mCPP alone, whereas clozapine slightly attenuated the effect of mCPP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Antipsychotic Agents; Behavior, Animal; Body Temperature; Clozapine; Dibenzothiepins; Exploratory Behavior; Haloperidol; Isoxazoles; Male; Mice; Motor Activity; Piperazines; Piperidines; Rats; Rats, Wistar; Receptors, Serotonin; Risperidone; Serotonin Antagonists; Serotonin Receptor Agonists

In vivo occupancy by typical or atypical antipsychotic drugs of dopamine D-1, D-2 and serotonin (5-HT)2 receptors in the membranes and slices of the rat brain was measured using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an irreversible antagonist at these receptor sites. In the membranes, the occupancy of D-1 receptors in the striatum by all tested drugs except cis-flupenthixol was minimal. Typical antipsychotic drugs such as chlorpromazine (10 mg/kg), haloperidol (1 mg/kg), cis-flupenthixol (1 mg/kg) and zotepine (5 mg/kg) occupied predominantly D-2 receptors in the striatum. Among atypical antipsychotic drugs, sulpiride (30 mg/kg) and amperozide (1 mg/kg) had no effect on the EEDQ-induced reduction in D-1, D-2 or 5-HT2 receptors, whereas clozapine (10 mg/kg), fluperlapine (10 mg/kg), risperidone (1 mg/kg), setoperone (0.25 mg/kg) and ORG 5222 (0.25 mg/kg) occupied mainly 5-HT2 receptors in the frontal cortex. In the slices, the occupancy by all tested drugs of D-1 receptors in the striatum, nucleus accumbens and substantia nigra was minimal with the exception of clozapine which showed about 30% occupancy in the substantia nigra. Typical antipsychotic drugs, chlorpomazine (10 mg/kg) and haloperidol (1 mg/kg) occupied predominantly D-2 receptors in the striatum and the nucleus accumbens. On the other hand, atypical antipsychotic drugs, clozapine (10 mg/kg) and risperidone (1 mg/kg), occupied mainly 5-HT2 receptors in the frontal cortex. These results suggest that there is a certain group of atypical antipsychotic drugs characterized by high occupancy of 5-HT2 receptors and low or minimum occupancy of D-2 receptors. These characteristics may be relevant to their weak potency in producing extrapyramidal side effects in man or catalepsy in rodents. Although we could find no clear regional differences in receptor occupancies by these antipsychotic drugs, further study are needed to elucidate this issue.

Topics: Animals; Antipsychotic Agents; Autoradiography; Brain; Chlorpromazine; Clozapine; Dibenzothiepins; Flupenthixol; Haloperidol; In Vitro Techniques; Isoxazoles; Male; Piperidines; Pyrimidinones; Rats; Rats, Wistar; Receptors, Dopamine; Receptors, Serotonin; Risperidone

The effects of the atypical neuroleptic zotepine in comparison with clozapine, risperidone and haloperidol were examined in tests related to the central 5-HT2 activity. Zotepine, as well as clozapine and risperidone, were very potent inhibitors of the 5-HTP-induced head twitches (the behavior mediated by 5-HT2 receptors) in mice, with rank order of potency risperidone > zotepine > clozapine; haloperidol used in high doses only slightly reduced the effect of 5-HTP. Zotepine, clozapine, risperidone and haloperidol antagonized the stimulatory effects of mCPP on the hind limb flexor reflex in spinal rats. As the mCPP-induced stimulation is considered to be mediated by 5-HT2 receptors, the above results provide further evidence for the 5-HT2 antagonistic activity of the drugs studied. Te rank order of potency in that test was the same as in the 5-HTP-induced head twitches (risperidone > zotepine > clozapine). The effect of haloperidol was somewhat unspecific, since its active doses were very high. In the model of hind limb flexor reflex of spinal rats, the anti-alpha 2-adrenergic effect was also tested. Clonidine-induced stimulation of the hind limb flexor reflex (an alpha 2-adrenergic effect) was antagonized by zotepine, clozapine, risperidone and haloperidol. It may be concluded that zotepine, clozapine and risperidone show an alpha 2-adrenergic antagonistic activity (order of potency: zotepine = risperidone > clozapine). The effect of haloperidol may be considered unspecific, since it is observed at high (cataleptic) doses only. In conclusion, it appears that zotepine, as well as clozapine and risperidone, are strong 5-HT2 antagonists, while haloperidol is not.

Topics: Animals; Antipsychotic Agents; Clozapine; Dibenzothiepins; Haloperidol; Isoxazoles; Male; Piperidines; Rats; Rats, Wistar; Receptors, Serotonin; Risperidone

The effects of biperiden and piroheptine on the serum level of zotepine were studied in 15 schizophrenic and 6 mentally retarded in-patients. Neither of these anticholinergic drugs affected the serum level of zotepine nor caused significant side-effects. In the schizophrenics the total scores on the BPRS did not change significantly with either combination of drugs.

Topics: Adult; Antipsychotic Agents; Biperiden; Dibenzocycloheptenes; Dibenzothiepins; Drug Therapy, Combination; Female; Humans; Intellectual Disability; Male; Middle Aged; Piperidines; Pyrrolidines; Schizophrenia; Schizophrenic Psychology

In a schizophrenic patient, hypothermia was caused by combined treatment with zotepine, biperiden, and fluphenazine, although combined treatment with zotepine and biperiden had caused no side effects. Other side effects closely resembled those in neuroleptic malignant syndrome.

Topics: Adult; Biperiden; Dibenzothiepins; Drug Therapy, Combination; Fluphenazine; Humans; Hypothermia; Male; Neuroleptic Malignant Syndrome; Piperidines; Schizophrenia