Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical profile of clozapine (CAS 5786-21-0) is characterized by superior efficacy in reducing the positive and negative symptoms of schizophrenia and a greatly reduced propensity to elicit acute extrapyramidal symptoms (e.g., Parkinsonian symptoms), long-term effects (e.g., tardive dyskinesia) and hyperprolactinemia. For these reasons clozapine is considered the prototypic atypical antipsychotic. The failure of clozapine to elevate serum prolactin concentrations may be related to the stimulatory effect of clozapine on tuberoinfundibular dopamine neurons and/or the failure of clozapine to achieve effective blockade of pituitary dopamine D2 receptors. The lack of acute blockade of striatal D2 receptors by clozapine and the failure of chronic clozapine treatment to suppress striatal dopamine release, relative to that produced by typical antipsychotic agents, may account for the lack of acute extrapyramidal symptoms and tardive dyskinesia, respectively, associated with the use of clozapine. Although the neurochemical substrates that subserve the unique preclinical and clinical profile of clozapine have not been determined unequivocally, clozapine and other purported atypical antipsychotic agents produce a greater antagonism of 5-HT2 receptors relative to D2 receptors than is the case for typical antipsychotics. Clozapine also exerts antagonism of D1 receptors. It is proposed that the selective interaction of clozapine among D2, D1, D4 and 5-HT2 receptors results in a distinctive alteration in the function of pre- and post-synaptic dopamine elements.
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PMID:Dopaminergic and serotonergic effects of clozapine. Implications for a unique clinical profile. 158 97

Dopamine agonists may be useful in the treatment of neuroleptic-induced hyperprolactinemia and movement disorders; it is a treatment approach that has been avoided for fear of inducing or exacerbating psychotic symptoms. The risks of giving dopamine agonists to psychiatric patients have been well documented in the literature. To further evaluate the psychotogenic effects of bromocriptine, a dopamine receptor agonist, we conducted a double-blind study in which 16 psychiatrically stable patients were treated for tardive dyskinesia with neuroleptics plus high doses of bromocriptine (N = 11) or placebo (N = 5) for 10 weeks. The diagnoses included schizophrenia, schizoaffective disorder, and major depression with psychotic features. Patients were evaluated weekly with the Brief Psychiatric Rating Scale and the Clinical Global Impression Scale during the 10-week treatment phase and for 8 weeks after medication was withdrawn. There were no statistically significant differences between active and placebo groups in behavioral ratings at baseline, week 10, and week 18. These results are compared with the findings of previous studies in which bromocriptine was given to psychiatric patients. Although the literature suggests that bromocriptine can induce or exacerbate psychosis in psychiatric patients, this occurs primarily in those with a psychotic diathesis and who are not currently receiving neuroleptic medication. Other important factors include the dose of bromocriptine, duration of treatment, and the clinical state of the patient at the time bromocriptine treatment is initiated. These results suggest that bromocriptine can be safely used in patients at risk for psychotic illnesses as long as patients are clinically stable and maintained on neuroleptics.
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PMID:The behavioral toxicity of bromocriptine in patients with psychiatric illness. 257 94

The cause of the amenorrhea that occurs in patients with hyperprolactinemia is unknown. The involvement of endogenous opioid peptides in the inhibition of GnRH release as a central factor leading to the hypogonadotropic state has been recently described. This study analyzed the LH response to opiate receptor blockade by naloxone (4 mg, iv) in groups of subjects with amenorrhea due to hyperprolactinemia of different etiologies. Patients presenting with a PRL-secreting pituitary adenoma (n = 7), idiopathic hyperprolactinemia (n = 9), or hyperprolactinemia during pharmacological treatment for schizophrenia (n = 5) were studied. Furthermore, to evaluate whether high circulating PRL levels influence the activity of the opioid system after the menopause, a group of seven postmenopausal subjects was tested before and 1 week after the administration of metoclopramide (10 mg, three times a day), a dopamine receptor antagonist. Normal premenopausal women (n = 6) served as controls. Naloxone significantly increased plasma LH levels in both prolactinoma and idiopathic hyperprolactinemic patients (P less than 0.01 vs. basal and placebo). In neither of those groups was a significant correlation found between the plasma LH response to naloxone and basal plasma PRL levels. In contrast to pathological hyperprolactinemia, blockade of opiate receptors did not significantly change LH secretion in either amenorrheic women with pharmacologically induced hyperprolactinemia or postmenopausal women. These results suggest that the effect of hyperprolactinemia on opioid modulation of LH secretion is related to the nature of the hyperprolactinemic state, supporting the existence of increased opioid inhibition of LH levels in pathological hyperprolactinemia.
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PMID:Differences in the opioid control of luteinizing hormone secretion between pathological and iatrogenic hyperprolactinemic states. 288 Aug 62

1. Interpretation of neuroendocrine studies in schizophrenia requires consideration of (a) the large number of variables that affect drug-induced endocrine responses (b) the effect of prior neuroleptic therapy (c) heterogeneity of schizophrenia (d) heterogeneity of receptors (e) uniqueness of the hypothalamic-pituitary axis (f) selectivity and pharmacokinetics of administered drugs. 2. Apomorphine increases growth hormone secretion by an effect on dopamine receptors that are not linked to adenylate cyclase and which are located outside the blood brain barrier. 3. Hypothalamic-pituitary histaminergic H2 and alpha-adrenergic function are unchanged in chronic schizophrenia. 4. Schizophrenic symptoms persist despite complete blockade of dopamine receptors modulating prolactin secretion. 5. Studies on dopamine receptors modulating prolactin secretion are unlikely to shed light on the pathophysiology of schizophrenia. 6. Screening for drugs which block apomorphine-induced growth hormone secretion but do not increase prolactin may provide a way of detecting anti-schizophrenic drugs which are devoid of side effects associated with hyperprolactinemia and which do not induce parkinsonism or tardive dyskinesia.
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PMID:Drug-induced growth hormone and prolactin responses in schizophrenia research. 613 95

Pergolide mesylate is a potent dopamine agonist that is being evaluated clinically in Parkinson disease, hyperprolactinemia, and other diseases. Pergolide activates both presynaptic and postsynaptic dopamine receptors, with some apparent selectivity for the presynaptic dopamine autoreceptors. In rats, low doses of pergolide (0.01 mg/kg or less, intraperitoneally) decreased dopamine turnover in brain, decreased serum prolactin concentration, and reduced blood pressure in spontaneously hypertensive rats. At somewhat higher doses (0.05 mg/kg or more, intraperitoneally), pergolide caused contralateral turning in nigrostriatal-lesioned rats, elevation of serum corticosterone, and hypermotility with stereotyped behavior. All of these actions are thought to be due to stimulation of dopamine receptors at various sites, but the data suggest that pergolide may have preferential affinity for presynaptic dopamine receptors. If low doses of pergolide can reduce dopaminergic transmission by activating presynaptic receptors that control dopamine release, then this action might be therapeutically useful in treating schizophrenia without causing tardive dyskinesia or in the treatment of tardive dyskinesia. The long duration of action of pergolide seen in animal and human studies could be an important advantage over some other dopamine agonists such as apomorphine.
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PMID:Degree of selectivity of pergolide as an agonist at presynaptic versus postsynaptic dopamine receptors: implications for prevention or treatment of tardive dyskinesia. 717 59

Osteoporosis, a very prevalent, potentially debilitating disease, is characterized by decreased bone mineral density (BMD). Decreased BMD has recently been reported in patients suffering from several mental disorders, including schizophrenia and major depression. In these patients the accelerated decrease in BMD can be attributed to drug-induced decreases in levels of estrogen and testosterone, to polydipsia and decreased calcium to smoking and alcoholism, and to increased activity of several interleukins as well as to hyperprolactinemia and hypercortisolemia. Several of these processes may be prevented or altered in order to prevent or delay decreased BMD.
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PMID:Accelerated osteoporosis in psychiatric patients: possible pathophysiological processes. 887 95

Treatment with standard antipsychotic medications causes side effects such as hyperprolactinemia and extrapyramidal symptoms. Because these side effects can cause noncompliance with antipsychotic medication and consequent relapse, they add to the morbidity of schizophrenia. A compound with antipsychotic efficacy but without the side effects of standard antipsychotic agents would improve compliance and treatment outcomes and enhance quality of life. Improved compliance, reduced relapse, and decreased hospitalization would also reduce the cost of treatment of schizophrenia. Seroquel (ICI 204,636), an atypical antipsychotic compound in Phase III development, was found to be well tolerated and effective in treating subjects with DSM-III-R schizophrenia in three Phase II clinical trials. Analysis of plasma prolactin concentrations obtained during these trials revealed that ICI 204,636 did not differ from placebo in its effect on plasma prolactin after up to 6 weeks of treatment; no significant difference was found in the degree of decline of plasma prolactin levels when subjects treated with ICI 204,636 and placebo were compared. A significant difference was found, however, between ICI 204,636- and chlorpromazine-treated subjects; prolactin levels in ICI 204,636-treated subjects fell to a greater degree than they did in chlorpromazine-treated subjects, however in all three trials, ICI 204,636 did not cause sustained elevation of prolactin.
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PMID:Plasma prolactin in schizophrenia subjects treated with Seroquel (ICI 204,636). 892 58

Olanzapine and risperidone, both second-generation antipsychotic agents, represent two different pharmacologic strategies. Although they share some in vitro properties, they differ by virtue of their chemical structure, spectrum of receptor binding affinities, animal neuropharmacology, pharmacokinetics, and in vivo neuroimaging profile. Based on such differences, it was hypothesized that the two compounds would show distinct safety and/or efficacy characteristics. To test this hypothesis, an international, multicenter, double-blind, parallel-group, 28-week prospective study was conducted with 339 patients who met DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. Results of the study indicated that both olanzapine and risperidone were safe and effective in the management of psychotic symptoms. However, olanzapine demonstrated significantly greater efficacy in negative symptoms (Scale for Assessment of Negative Symptoms summary score), as well as overall response rate (> or = 40% decrease in the Positive and Negative Syndrome Scale total score). Furthermore, a statistically significantly greater proportion of the olanzapine-treated than risperidone-treated patients maintained their response at 28 weeks based on Kaplan-Meier survival curves. The incidence of extrapyramidal side effects, hyperprolactinemia, and sexual dysfunction was statistically significantly lower in olanzapine-treated than risperidone-treated patients. In addition, statistically significantly fewer adverse events were reported by olanzapine-treated patients than by their risperidone-treated counterparts. Thus, the differential preclinical profiles of these two drugs were also evident in a controlled, clinical investigation. Olanzapine seemed to have a risk-versus-benefit advantage.
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PMID:Double-blind comparison of olanzapine versus risperidone in the treatment of schizophrenia and other psychotic disorders. 979 Jan 65

Ninety patients with schizophrenia or schizoaffective disorder according to DSM-III-R criteria participated in this double-blind, exploratory, dose-ranging trial. After a single-blind washout period of 4 to 7 days, patients were randomly assigned to receive one of four fixed doses of the new antipsychotic, ziprasidone 4 (N = 19), 10 (N = 17), 40 (N = 17), or 160 (N = 20) mg/day or haloperidol 15 mg/day (N = 17) for 4 weeks. A dose-response relationship among ziprasidone groups was established for improvements in Clinical Global Impression Severity (CGI-S) score (p = 0.002) but not in Brief Psychiatric Rating Scale (BPRS) total score (p = 0.08). The intent-to-treat analysis of mean changes from baseline in the BPRS total, BPRS Psychosis core, and CGI-S scores demonstrated that ziprasidone 160 mg/day was comparable with haloperidol in reducing overall psychopathology and positive symptoms and was superior to ziprasidone 4 mg/day. Despite the small sample size and short duration of the trial, the improvement in CGI-S with both ziprasidone 160 mg/day and haloperidol 15 mg/day was statistically significantly greater than with ziprasidone 4 mg/day (p = 0.001 andp = 0.005, respectively). The percentage of patients classified as responders on both the BPRS total (> or = 30% improvement) and CGI-Improvement (score of 1 or 2) scales in the ziprasidone 160 mg/day group was similar to that in the haloperidol group and nonsignificantly greater than that in the ziprasidone 4 mg/day group. On all assessments of clinical efficacy, the improvements associated with ziprasidone 4 mg/day, 10 mg/day, and 40 mg/day were similar. Concomitant benztropine use at any time during the study was less frequent with ziprasidone 160 mg/day (15%) than with haloperidol (53%). Haloperidol was associated with a sustained hyperprolactinemia, unlike ziprasidone, where only transient elevations in prolactin that returned to normal within the dosing interval were observed. Ziprasidone was well tolerated, and the incidence of adverse events was similar in all groups. The results of this study suggest that ziprasidone 160 mg/day is as effective as haloperidol 15 mg/day in reducing overall psychopathology and positive symptoms of an acute exacerbation of schizophrenia or schizoaffective disorder but has a lower potential to induce extrapyramidal symptoms.
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PMID:An exploratory haloperidol-controlled dose-finding study of ziprasidone in hospitalized patients with schizophrenia or schizoaffective disorder. 969 Jun 95

The authors describe the case of a patient with treatment-resistant schizophrenia who became pregnant after switching from conventional neuroleptic medications to clozapine, an atypical antipsychotic medication that does not cause hyperprolactinemia. Gestational diabetes, possibly exacerbated by clozapine, complicated management of her pregnancy. Comprehensive community support and psychiatric rehabilitation, combined with a positive response to clozapine, contributed to satisfying the patient's goal of having a healthy baby and being able to take the baby home to live with her and her husband.
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PMID:Pregnancy of a patient treated with clozapine. 971 1


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