clozapine and Pituitary-Neoplasms

Topics: Adult; Antipsychotic Agents; Bromocriptine; Clozapine; Dopamine Agonists; Dopamine Antagonists; Drug Antagonism; Female; Haloperidol; Humans; Hyperprolactinemia; Pituitary Neoplasms; Prolactin; Prolactinoma; Schizophrenia

To analyze the disproportionality of reporting of hyperprolactinemia, galactorrhea, and pituitary tumors with seven widely used antipsychotic drugs.. Retrospective pharmacovigilance study.. United States Food and Drug Administration's Adverse Event Reporting System (AERS) database.. We initially identified higher-than-expected postmarketing reports of pituitary tumors associated with risperidone, a potent dopamine D2-receptor antagonist antipsychotic, by analyzing reporting patterns of these tumors in the AERS database. To further examine this association, we analyzed disproportionate reporting patterns of pituitary tumor reports for seven antipsychotics with different affinities for blocking D2 receptors: aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and haloperidol.. To conduct both of these analyses, we used the Multi-item Gamma Poisson Shrinker (MGPS) data mining algorithm applied to the AERS database. The MGPS uses a Bayesian model to calculate adjusted observed:expected ratios of drug-adverse event associations (Empiric Bayes Geometric Mean [EBGM] values) in huge drug safety databases. The higher the adjusted reporting ratio, or EBGM value, the greater the strength of the association between a drug and an adverse event. Risperidone had the highest adjusted reporting ratios for hyperprolactinemia (EBGM 34.9, 90% confidence interval [CI] 32.8-37.1]), galactorrhea (EBGM 19.9, 90% CI 18.6-21.4), and pituitary tumor (EBGM 18.7, 90% CI 14.9-23.3) among the seven antipsychotics, and one of the highest scores for all drugs in the AERS database. Some tumors were associated with visual field defects, hemorrhage, convulsions, surgery, and severe (>10-fold) prolactin elevations. The EBGM values for risperidone for these adverse events were higher in women, but high EBGM values for these events were also seen in men and children. Moreover, the rank order of the EBGM values for pituitary tumors corresponded to the affinities of these seven drugs for D2 receptors.. Treatment with potent D2-receptor antagonists, such as risperidone, may be associated with pituitary tumors. These findings are consistent with animal (mice) studies and raise the need for clinical awareness and longitudinal studies.

Topics: Adolescent; Adverse Drug Reaction Reporting Systems; Amenorrhea; Antipsychotic Agents; Aripiprazole; Benzodiazepines; Child; Clozapine; Dibenzothiazepines; Female; Galactorrhea; Gynecomastia; Haloperidol; Humans; Hyperprolactinemia; Male; Olanzapine; Piperazines; Pituitary Neoplasms; Quetiapine Fumarate; Quinolones; Retrospective Studies; Risperidone; Sex Factors; Thiazoles; United States; United States Food and Drug Administration

Three patients with psychoses and concomitant prolactin-secreting pituitary tumours are described. Patients A and B had bipolar and schizoaffective disorders, respectively. They had both been treated with neuroleptics for 20 years before the prolactinomas were revealed. Patient C developed a paranoid psychosis after two years of continuous bromocriptine treatment for a pituitary tumour. In patient A the prolactin level was successfully normalized and a good antipsychotic effect was maintained by combined therapy with haloperidol and quinagolide but not bromocriptine. In patient B the prolactinoma was removed by surgery, in view of the serious nature of the psychotic disorder, to avoid psychotic relapse by treatment with a dopamine agonist. In patient C a good result was obtained with the combination of clozapine and bromocriptine. These case reports support the view that neuroleptics being dopamine antagonists and dopamine agonistic agents which are the primary treatment of prolactinomas can cancel out each other's effects. The combination of clozapine and quinagolide is recommended as the treatment of choice for most patients.

Topics: Adult; Aminoquinolines; Antipsychotic Agents; Bipolar Disorder; Bromocriptine; Clozapine; Comorbidity; Dopamine Agonists; Dopamine Antagonists; Drug Interactions; Drug Therapy, Combination; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Psychoses, Substance-Induced; Psychotic Disorders

We investigated the effects of oleamide, a fatty acid amide isolated from the cerebrospinal fluid of sleep-deprived cats, on serotonin receptor-mediated signaling in cultured mammalian cells. Oleamide demonstrated opposing effects on 5-HT2A and 5-HT7 receptors, in rat pituitary cells and transfected HeLa cells, respectively. Oleamide caused a potentiation of 5-HT-elicited inositol phosphate formation mediated by the 5-HT2A receptor, but inhibited the effects of 5-HT on cAMP production mediated by the 5-HT7 receptor. In addition, oleamide alone caused a significant increase in cAMP accumulation that was dependent on the presence of the 5-HT7 receptor, but was not blocked by clozapine. These results demonstrate that oleamide can have diverse effects on 5-HT-mediated signal transduction at different subtypes of mammalian 5-HT receptors. Additionally, our data suggest that oleamide may act at an allosteric site on the 5-HT7 receptor and can elicit functional responses via activation of this site.

Topics: Animals; Cats; Cerebrosides; Clozapine; Cyclic AMP; Fatty Acids, Monounsaturated; Fluorescent Dyes; HeLa Cells; Humans; Inositol Phosphates; Oleic Acids; Pituitary Gland; Pituitary Neoplasms; Quaternary Ammonium Compounds; Rats; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; Recombinant Proteins; Serotonin; Signal Transduction; Sleep Deprivation; Transfection

Topics: Adult; Antipsychotic Agents; Bromocriptine; Clozapine; Dopamine Agonists; Drug Therapy, Combination; Female; Humans; Pituitary Neoplasms; Prolactinoma; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Adolescent; Clozapine; Female; Humans; Neurocognitive Disorders; Pituitary Neoplasms; Prolactin; Prolactinoma

Clozapine is an antipsychotic drug which is unusual in that it has no dopamine receptor-blocking activity. Previous studies gave conflicting results whether administration of clozapine induces hyperprolactinemia. In the present study it was shown that a wide concentration range of clozapine does not interfere with dopamine-mediated inhibition of prolactin (PRL) secretion by normal cultured rat pituitary cells. This in contrast to other neuroleptics, like haloperidol and trifluoperazine. Clozapine does also not antagonize norepinephrine-mediated inhibition of PRL secretion. Clozapine exerts at micromolar concentrations a direct inhibitory action on PRL release by cultured normal rat pituitary cells. In cultured rat pituitary tumor cells, these high concentrations of clozapine directly inhibit PRL release as well as the DNA content of the cells, suggesting a direct antimitotic action. In this model clozapine was about 5-10 times less potent than trifluperazine. Clozapine and trifluoperazine exert an additive inhibitory action both on PRL release and on the DNA content of the pituitary tumor cells. It is concluded that clozapine does not interfere at the pituitary level with dopamine-mediated inhibition of PRL release. At micromolar concentrations clozapine may act on lactotrophs as a calmodulin-inhibitor. These observations suggest that the transient PRL-releasing effects which have been observed in both animal and human studies after clozapine administration are mediated via supra-pituitary actions of the drug.

Topics: Animals; Cells, Cultured; Clozapine; Dibenzazepines; Dopamine; Dose-Response Relationship, Drug; Female; Male; Norepinephrine; Pituitary Gland; Pituitary Neoplasms; Prolactin; Rats; Rats, Inbred BUF; Trifluoperazine; Tumor Cells, Cultured