clozapine and Erectile-Dysfunction

Priapism is a prolonged, usually painful, and persistent penile erection not usually associated with sexual stimuli, resulting from a disturbance in the normal regulatory mechanisms that initiate and maintain penile flaccidity. This infrequent adverse event of antipsychotic medication use requires emergency evaluation and has potentially serious long-term sequelae including erectile dysfunction. Clinicians prescribing antipsychotic medications should be aware of this rare but serious adverse event.. A computerized search, using the MEDLINE database (1966-summer 2000), located cases of priapism associated with most conventional antipsychotics as well as with clozapine, risperidone, and olanzapine. The search included no restrictions on languages. Keywords included priapism combined with antipsychotic agents and the names of the currently available atypical antipsychotics. Twenty-nine publications were located using these parameters. Additional publications were reviewed for general background on pathophysiology, evaluation, and management. The quality of the evidence reviewed is limited by the observational and uncontrolled nature of case reports, case series. and review articles.. Psychotropic-induced priapism is currently believed to be caused by the alpha1-adrenergic antagonism of these medications. Detumescence is sympathetically mediated, and alpha1-adrenergic antagonism (within the corpora cavernosa) inhibits detumescence. The propensity of individual antipsychotics to induce priapism can presumably be estimated on the basis of alpha1adrenergic blockade affinities. Of the conventional antipsychotics, chlorpromazine and thioridazine have the greatest alpha1-adrenergic affinity and have been most frequently reported to be associated with priapism. Of the atypical antipsychotics, risperidone has greater alpha1-adrenergic affinity, although 3 of the 5 currently U.S. Food and Drug Administration (FDA)-approved atypicals have been reported to be associated with priapism.. Virtually all antipsychotic medications have been reported to rarely cause priapism due to their alpha-adrenergic antagonism. This adverse event should be considered a urologic emergency. Clinicians should be familiar with this infrequent serious adverse event of antipsychotic medications.

Topics: Antipsychotic Agents; Benzodiazepines; Circadian Rhythm; Clozapine; Erectile Dysfunction; Female; Forensic Psychiatry; Humans; Male; Olanzapine; Pirenzepine; Priapism; Psychotic Disorders; Risperidone

The International Schizophrenia Outpatient Health Outcomes study, IC-SOHO is a three-year international observational study that investigates clinical and health outcomes of antipsychotic treatments. 7658 outpatients treated for schizophrenia were enrolled in the study, who needed an antipsychotic therapy to initiate or switch. The primary analysis compared the group taking olanzapine with the group taking any other antipsychotics, while the secondary comparison was performed between those treated with olanzapine and those with risperidone. Efficacy analysis was carried out based on changes in Clinical Global Impression of Severity scale (CGI-S), which was performed at a global symptom level, as well as with respect to the patients' positive, negative, cognitive and depressive symptoms. In addition, adverse events were also evaluated. Results of the analysis of the 3- and 6-month data from Hungary are disclosed in this publication. 200 patients were enrolled in the country. Demographics of the treatment groups were not significantly different. At 3 and 6 months after treatment initiation, there were no significant between-group differences in improvement of global symptomatology, however, cognitive symptoms improved more in the Olanzapine-group compared to those taking other antipsychotics (p<0.05). In patients showing Extrapyramidal Symptoms (EPS) at baseline, these symptoms finished to a greater extent among those receiving olanzapine than in those receiving other antipsychotics (after 6 months D<0.0001). Half a year later, significantly less patients showed extrapyramidal adverse events (p=0,0007), and the previous EPS terminated to a greater extent (p=0.0016) in the olanzapine group, as compared to those taking risperidone. No between-group differences were found in changes of sexual functions, as well as of weight and Body Mass Index measures. Switching antipsychotic initiated at study baseline, and adding-on one or more other antipsychotic to the initial one, were significantly less frequent in the Olanzapine-group compared to those initiated other antipsychotics. In the first 3 months, treatment compliance was significantly higher with olanzapine therapy than with other antipsychotic treatments, and with risperidone respectively. Results from the Hungarian sample correspond with results from higher analysis levels of wider patient populations of IC-SOHO study. Olanzapine showed outstanding efficacy in lessening cognitive disturbances and global cli

Topics: Adult; Aggression; Antipsychotic Agents; Basal Ganglia Diseases; Benzodiazepines; Clozapine; Dibenzothiazepines; Erectile Dysfunction; Female; Galactorrhea; Gynecomastia; Haloperidol; Humans; Hungary; International Cooperation; Libido; Male; Menstruation Disturbances; Middle Aged; Olanzapine; Outpatients; Patient Admission; Patient Compliance; Prospective Studies; Quetiapine Fumarate; Risperidone; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index

A series of novel 2-[(4-phenylpiperazin-1-yl)methyl]imidazoazines and aza-analogues were prepared and screened at selected dopamine, serotonin, and adrenergic receptor subtypes. 2-Substituted imidazopyridines and pyridazines presented high affinities and selectivities for D4 dopamine receptors. Whereas functional experiments indicated neutral antagonists or weak partial agonist effects for most of the target compounds, the 2-methoxyphenyl substituted 2-piperazinylmethylimidazopyridine 3c (PIP3EA) displayed substantial agonist efficacy in mitogenesis experiments and GTPgammaS binding tests, resulting in EC50 values of 3.0 (46%) and 4.5 nM (57%), respectively. Our D4 agonist 3c induced penile erection in vivo when administered to rats. This effect was inhibited by L-745,870 a D4 selective antagonist, confirming the mechanistic pathway.

Topics: Animals; Cattle; CHO Cells; Cricetinae; Cricetulus; Erectile Dysfunction; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Imidazoles; Ligands; Male; Mitosis; Penile Erection; Piperazines; Pyridines; Pyrroles; Radioligand Assay; Rats; Receptors, Dopamine D4; Structure-Activity Relationship

A new series of dopamine D4 receptor agonists, 1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes, was designed through the modification of known dopamine D4 receptor agonist PD 168077. Replacement of the amide group with a methylene-oxime moiety produced compounds with improved stability and efficacy. Structure-activity relationsips (SAR) of the aromatic ring linked to the N-4-piperazine ring confirmed the superiority of 2-pyridine as a core for D4 agonist activity. A two-methylene linker between the oxime group and the N-1-piperazine ring displayed the best profile. New dopamine D4 receptor agonists, exemplified by (E)-1-(4-chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (59a) and (E)-1-(3-chloro-4-fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (64a), exhibited favorable pharmacokinetic profiles and showed oral bioavailability in rat and dog. Subsequent evaluation of 59a in the rat penile erection model revealed in vivo activity, comparable in efficacy to apomorphine. Our results suggest that the oximes provide a novel structural linker for 4-arylpiperazine-based D4 agonists, possessing leadlike quality and with potential to develop a new class of potent and selective dopamine D4 receptor agonists.

Topics: Animals; Benzamides; Binding Sites; Cell Line; Crystallography, X-Ray; Disease Models, Animal; Drug Evaluation, Preclinical; Erectile Dysfunction; Ferrets; Humans; Male; Models, Molecular; Molecular Structure; Oximes; Piperazines; Rats; Rats, Wistar; Receptors, Dopamine D4; Stereoisomerism; Structure-Activity Relationship

The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.

Topics: Action Potentials; Administration, Oral; Animals; Benzamides; Biological Availability; Cell Line; Cyclic N-Oxides; Dogs; Erectile Dysfunction; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Haplorhini; Humans; In Vitro Techniques; Male; Patch-Clamp Techniques; Purkinje Fibers; Rats; Receptors, Dopamine D4; Structure-Activity Relationship

The novel antipsychotic medications offer a more favorable extrapyramidal side effect profile than conventional agents. It is uncertain that the novel antipsychotics have a benefit in terms of sexual side effects.. We prospectively administered a survey of sexual functioning to 25 male patients with DSM-IV schizophrenia, taking conventional and novel antipsychotics. Contrasts were made between three treatment groups: clozapine (CLOZ), risperidone (RIS), and a combined haloperidol/fluphenazine (HAL/FLU) group.. A decrease in overall sexual functioning was reported in all medication groups (40-71%). The majority of subjects taking RIS or HAL/FLU reported a decline in one or more aspects of sexual functioning. Examining specific aspects of sexual functioning revealed that, a decline in sexual interest was significantly less common on CLOZ compared to RIS (0 vs. 64%; chi(2)=6.1, df=1, p=0.01) or HAL/FLU (0 vs. 67%; chi(2)=5.2, df=1, p=0.02), while a decline in the erectile frequency was significantly more common on RIS compared to CLOZ (40 vs. 93%; chi(2)=6.2, df=1, p=0.01) or HAL/FLU (50 vs. 93%; chi(2)=4.8, df=1, p=0.03) (0%). For enjoyment of orgasm and ejaculatory volume, significantly fewer CLOZ compared to RIS subjects reported a decline (20 vs. 86%; chi(2)=7.4, df=1, p=0.01).. Sexual side effects are common clinically pertinent adverse effects associated with both novel and conventional antipsychotic medications. They deserve increased attention in clinical work and future research with emerging antipsychotic drugs.

Topics: Adult; Antipsychotic Agents; Clozapine; Erectile Dysfunction; Fluphenazine; Haloperidol; Humans; Male; Middle Aged; Prospective Studies; Psychiatric Status Rating Scales; Risperidone; Schizophrenia; Schizophrenic Psychology; Sexual Behavior