ergoline and Schizophrenia

The aim of this study was to evaluate the effect on the activity of the hypothalamic-pituitary dopaminergic system of two new atypical antipsychotic drugs: the ergoline derivative SDZ HDC-912, which is a dopamine (DA) D2 receptor partial agonist; and the quinolinone derivative OPC-4392, which acts as an agonist at presynaptic DA autoreceptors and as an antagonist at post-synaptic D2 receptors. The effects of both compounds were compared to the effects of the benzamide derivative amisulpride. Prolactin (PRL) and growth hormone (GH) levels before and after challenge with apomorphine (Apo), a dopaminergic agonist, were determined after at least 2 weeks washout and again after 1 month of treatment in DSM-III-R schizophrenic inpatients. SDZ HDC-912 significantly decreased Apo-induced PRL inhibition, and tended to decrease PRL secretion and Apo-induced GH stimulation. OPC-4392 induced a significant decrease in baseline PRL and in Apo-induced PRL suppression, and a non-significant decrease in Apo-induced GH stimulation. The neuroendocrine profiles of these two compounds agree with their dopaminergic properties; however, the decrease in PRL basal level differentiates the two drugs from neuroleptic agents.

Topics: Adult; Amisulpride; Antipsychotic Agents; Apomorphine; Dopamine Agonists; Ergolines; Female; Growth Hormone; Humans; Male; Neurosecretory Systems; Piperazines; Prolactin; Quinolones; Schizophrenia; Sulpiride

Topics: Acetonitriles; Adult; Antiparkinson Agents; Antipsychotic Agents; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Drug Therapy, Combination; Ergolines; Female; Fluphenazine; Humans; Middle Aged; Parkinson Disease, Secondary; Prolactin; Schizophrenia

Based on "quantitative pharmaco-EEG" using computer-analyzed EEG (CEEG) measurements, unknown CNS effects of lisuride hydrogen maleate (LHM) were established. CEEG profiles of LHM in low dosages (less than or equal to 10 mcg) are similar to CNS "inhibitory" compounds, while in higher dosages (25 mcg to 100 mcg) they resemble "psychostimulant" compounds. By measuring the brain function using computer period analysis of cerebral biopotentials, dose-efficacy relations were found (in the range of 25-75 mcg) which suggest the bioavailability of LHM at the CNS level. By comparing the CEEG profiles of LHM with the previously studied compounds, five different clinical uses of LHM were predicted. The pilot trials suggest that LHM may have therapeutic potentials in patients with "aging" and/or organic brain syndromes, and in children with behavioral disturbances.

Topics: Adolescent; Adult; Aged; Biological Availability; Child; Child, Preschool; Clinical Trials as Topic; Computers; Dementia; Dextroamphetamine; Diazepam; Drug Evaluation; Electroencephalography; Ergolines; Humans; Hyperkinesis; Isocarboxazid; Methylphenidate; Middle Aged; Migraine Disorders; Obesity; Pilot Projects; Psychophysiologic Disorders; Psychotropic Drugs; Schizophrenia; Urea

Antipsychotic medications are associated to different degrees with sexual dysfunction mainly through their potential to induce hyperprolactinemia. Prolactin (PRL) secretion is mainly regulated by the hypothalamic dopaminergic systems. We conducted this 6-month, parallel-group study to prospectively investigate the effects of the dopamine agonist cabergoline on sexual dysfunction in clinically stable patients with schizophrenia (DSM-IV, AP 194) and hyperprolactinemia (PRL > 20 ng/ml for men and PRL > 25 ng/ml for women). In total 80 patients were enrolled; 33 were receiving risperidone, 17 haloperidol, 11 amisulpride, and 8 risperidone microspheres long acting. Based on PRL levels (< 50, 50-99, or > 100 ng/ml), patients were assigned in 3 cabergoline doses (0.25, 0.5, and 1 mg/day in 38, 23, and 19 patients, respectively). The psychopathology was evaluated using the Positive and Negative Syndrom Scale (PANSS), and sexual dysfunction was evaluated using the Arizona Sexual Experiences Scale (ASEX). PRL levels were reduced in all patients, from 73.3 (± 46.8) to 42.0 (± 27.8) at Month 3 and 27.1 (± 20.4) at Month 6 (p < .001). ASEX scores declined from 19.1 (± 5.1) to 17.6 (± 5.5) at Month 3 and 15.0 (± 6.5) at Month 6 (p < .001). PANSS scores were reduced in the third and in the sixth month (p = .001 at 6 month vs. baseline). The decrease in PRL was not statistically different between groups. Our data suggest that cabergoline administration to clinically stable patients with schizophrenia may improve sexual functioning without adversely affecting their psychopathologic status, provided that the dose has been suited to the severity of the hyperprolactinemia.

Topics: Adult; Amisulpride; Antipsychotic Agents; Cabergoline; Diagnostic and Statistical Manual of Mental Disorders; Dopamine Agonists; Dose-Response Relationship, Drug; Ergolines; Female; Haloperidol; Humans; Hyperprolactinemia; Longitudinal Studies; Maintenance Chemotherapy; Male; Middle Aged; Prolactin; Prospective Studies; Risperidone; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Sexual Dysfunction, Physiological; Sulpiride

Hyperprolactinemia causes hypogonadotrophic hypogonadism. Hyperprolactinemia can be pre-existing in some patients with schizophrenia. Dopamine is the most important prolactin-inhibiting factor, and dopaminergic hyperactivity has been implicated in the pathophysiology of psychosis.. Since dopamine is a prolactin-inhibiting factor and dopamine imbalanced has been implicated in the pathophysiology of psychotic disorders, we investigated the probable relationship between hyperprolactinemia and the development of psychotic symptoms, in a patient with hypogonadism due to hyperprolactnemia and subsequent first episode of psychosis. Since dopamine is a prolactin-inhibiting factor and dopamine imbalance has been implicated in the pathophysiology of psychotic disorders, we investigated the probable relationship between hyperprolactinemia and the development of psychotic symptoms.. We present the case of a patient with hypogonadism secondary to chronic, untreated hyperprolactinemia who developed acute psychotic symptoms.. Psychotic symptoms resolved soon after treatment with aripiprazole in conjunction with cabergoline, with a concomitant decrease in serum prolactin level.. This is an interesting case illustrating a complicated relationship among hypogonadism secondary to a prolactinoma and dopamine and psychosis.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Cabergoline; Ergolines; Humans; Hyperprolactinemia; Hypogonadism; Male; Obesity, Morbid; Piperazines; Pituitary Neoplasms; Prolactin; Prolactinoma; Psychotic Disorders; Quinolones; Schizophrenia

Abnormalities in both the hippocampal region and in serotonergic transmission are evident in patients with schizophrenia. We previously found that rats with serotonergic lesions targeting the dorsal hippocampus show altered psychotropic drug-induced hyperlocomotion and prepulse inhibition (PPI), behavioural paradigms relevant to aspects of schizophrenia. The present study explored the effect of serotonin depletion (>70%) along the dorsoventral axis of the hippocampus, or of partial serotonin depletion (∼50%) in the ventral hippocampus, on PPI modulation by acute antipsychotic drug treatment. We also used receptor binding autoradiography to investigate the neurochemical basis of behavioural effects. Following micro-injection of 5,7-dihydroxytryptamine, neither hippocampal serotonin depletion or partial serotonin depletion in the ventral hippocampus altered baseline PPI, startle magnitude or startle habituation. Acute treatment with clozapine or haloperidol had minimal effects on PPI in these lesioned rats or sham-operated controls. In contrast, risperidone treatment increased PPI to a significantly greater extent in rats with hippocampal serotonin depletion, an effect which was most prominent at low prepulse intensities. Partial serotonin depletion in the ventral hippocampus did not alter PPI modulation by risperidone. Neither type of serotonergic lesion altered the densities of 5-HT(1A) or 5-HT(2A) receptors in the hippocampus; serotonin transporters or 5-HT(1A) autoreceptors on raphe cell bodies; or dopamine transporters, D(1) or D(2) receptors in forebrain regions efferent to the hippocampus and implicated in schizophrenia, such as the nucleus accumbens. However, levels of [(3)H]mesulergine binding to 5-HT(2C) receptors were increased by approximately 70% in the dorsal hippocampus of rats with serotonin depletion in this region, while those in the ventral hippocampus were unaffected. Therefore, despite intact baseline PPI, abnormal PPI regulation in rats with >70% serotonin depletion in the hippocampus was unmasked by acute risperidone treatment. Selective upregulation of 5-HT(2C) receptors in the dorsal, but not ventral, hippocampus of these lesioned rats suggests that hippocampal 5-HT(2C) receptors vary in their adaptability to changes in serotonergic tone along the dorsoventral axis. These findings suggest that 5-HT(2C) receptors in the dorsal hippocampus may contribute to risperidone-induced enhancement of PPI.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Ergolines; Hippocampus; Male; Nerve Tissue Proteins; Neural Inhibition; Neurons; Organ Specificity; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C; Reflex, Startle; Risperidone; Schizophrenia; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists

Topics: Administration, Oral; Adult; Antipsychotic Agents; Aripiprazole; Cabergoline; Clonazepam; Dopamine Agonists; Drug Therapy, Combination; Ergolines; Female; Follow-Up Studies; Humans; Patient Care Team; Piperazines; Pituitary Neoplasms; Prolactin; Prolactinoma; Quinolones; Schizophrenia

Aripiprazole is the first dopamine D(2) receptor partial agonist approved for use in schizophrenia and bipolar disorder. Other partial agonists have failed in various stages of development, either for reasons of poor tolerability or lack of efficacy. We conducted an in vitro comparative analysis between aripiprazole, bifeprunox, SDZ 208-912, OPC-4392 and ACR16 in attempt to correlate specific pharmacological properties with clinical outcome. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of this inhibition produced by dopamine in clonal CHO cell lines expressing high and low densities of human dopamine D(2L) and D(2S) receptors. In cells expressing high receptor densities, all drugs except ACR16 predominantly behaved as agonists. However, in cells expressing low receptor densities, all drugs showed significantly lower maximal effects than dopamine. Aripiprazole's intrinsic activity was lower than that observed with bifeprunox and OPC-4392, and higher than that of SDZ 208-912. Aripiprazole's antagonist activity was greater than that of bifeprunox and OPC-4392, and less than that of SDZ 208-912. In conclusion, our data suggests that aripiprazole's unique intrinsic activity profile may account for its demonstrated clinical efficacy in the treatment of both positive and negative symptoms of schizophrenia, as well as its demonstrated low liability for parkinsonism and hyperprolactinemia. A higher degree of intrinsic activity, and lower relative antagonist activity, such as that observed with bifeprunox and OPC-4392 may translate into a clinically suboptimal improvement of positive symptoms. SDZ 208-912's intrinsic activity may be lower than the optimal level needed to minimize extrapyramidal symptoms.

Topics: Animals; Aripiprazole; Benzoxazoles; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Ergolines; Humans; Piperazines; Quinolones; Radioligand Assay; Receptors, Dopamine D2; Schizophrenia

D(2) blockers, including the atypical antipsychotic risperidone, induce hyper-prolactinemia in a significant number of patients treated. The endocrine and sexual side effects related to hyperprolactinemia significantly impair tolerability and compliance in patients, including those with a good response to risperidone. This pilot study aimed to evaluate the efficacy and tolerability of a low dose of cabergoline, a D(2) agonist, in the treatment of risperidone-induced hyperprolactinemia.. Nineteen male and female DSM-IV-defined schizophrenic patients who were clinical responders to risperidone but were suffering from symptomatic hyperprolactinemia were treated with cabergoline, 0.125 to 0.250 mg/week for 8 weeks. Plasma prolactin level was assessed at baseline and at the end of the study. Data were collected from January 2002 to April 2003.. After cabergoline treatment, the mean decrease in plasma prolactin levels was statistically significant (p <.05) for the total sample, and 11 patients showed remission of clinical signs with prolactin values within the normal range. No side effect was observed or reported, and the patients' psychopathology was unchanged.. Results suggest that low-dose cabergoline treatment of risperidone-induced hyperprolactinemia may be safe and clinically effective in a relevant number of patients.

Topics: Adult; Antipsychotic Agents; Cabergoline; Dopamine Agonists; Dose-Response Relationship, Drug; Ergolines; Female; Humans; Hyperprolactinemia; Male; Middle Aged; Prolactin; Receptors, Dopamine D2; Risperidone; Schizophrenia; Schizophrenic Psychology

We determined cabergoline and L-dopa in human plasma using liquid chromatography-mass spectrometry with tandem mass spectrometry (LC-MS-MS). The deproteinized plasma samples with organic solvent or acid were analyzed directly by reversed-phase liquid chromatography. Using multiple reaction monitoring (MRM, product ions m/z 381 of m/z 452 for cabergoline and m/z 152 of m/z 198 for L-dopa) on LC-MS-MS with electrospray ionization (ESI), cabergoline and L-dopa in human plasma were determined. Calibration curves of the method showed a good linearity in the range 5-250 pg/ml for cabergoline and 1-200 ng/ml for L-dopa, respectively. The limit of determination was estimated to be approximately 2 pg/ml for cabergoline and approximately 0.1 ng/ml for L-dopa, respectively. The method was applied to the analysis of cabergoline and L-dopa in plasma samples from patients treated with these drugs. The precision of analysis showed coefficients of variation ranging from 3.8% to 10.5% at cabergoline concentration of 13.8-26.2 pg/ml and from 2.9% to 8.9% at an L-dopa concentration of 302.5-522.1 ng/ml in patient plasma. As a result, the procedure proved to be very suitable for routine analysis.

Topics: Adult; Cabergoline; Case-Control Studies; Chromatography, Liquid; Dopamine Agonists; Ergolines; Humans; Levodopa; Middle Aged; Reproducibility of Results; Schizophrenia; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization

Topics: Animals; Antipsychotic Agents; Biological Availability; CHO Cells; Cricetinae; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Ergolines; Humans; Molecular Structure; Piperazines; Protein Binding; Quinpirole; Receptors, Adrenergic; Receptors, Dopamine D4; Receptors, Serotonin; Schizophrenia; Sulfonamides

Topics: Antipsychotic Agents; Dopamine Agonists; Dopamine Antagonists; Ergolines; Quinpirole; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Tetrahydronaphthalenes

The antipsychotic effects of dopaminergic antagonists suggest dopaminergic hyperactivity plays a role in schizophrenia. However, an elevated number of D2 dopamine receptors in the left putamen of non-treated schizophrenics has been reported which is consistent with a diminution of dopaminergic transmission in the ventral striatum. Morphological and functional studies have shown marked alterations in the left medial temporal lobe (entorhinal cortex, hippocampus, parahippocampus gyrus) of schizophrenics. As the entorhinal cortex and the ventral hippocampus project to the ventral striatum, the functional relationship between left temporal structures and the left ventral striatum may be impaired in schizophrenics. To assess the validity of this hypothesis, we investigated the existence of a preferentially left hemispheric interdependency between dopaminergic pathways in male rats. We found that dopaminergic projections in the entorhinal cortex and the ventral hippocampus regulate dopaminergic transmission in the nucleus accumbens, particularly in the left hemisphere. Temporal D2 dopamine receptors seem to be primarily involved in this effect. This lateralized interdependent functioning appears structurally based. These results may provide new insights into the pathophysiology of schizophrenic psychoses.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Corpus Striatum; Dopamine; Dopamine Agents; Dopamine D2 Receptor Antagonists; Ergolines; Functional Laterality; Hippocampus; Humans; Male; Nucleus Accumbens; Quinpirole; Raclopride; Rats; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Synaptic Transmission; Temporal Lobe; Time Factors

Rats with limbic system damage display increases in responsivity to sensory stimulation and changes in the sensitivity to amphetamine, suggesting that their condition may parallel that of human schizophrenia. This experiment examined locomotion and stereotyped behavior in mature, male rats that had received aspirative lesions of the hippocampus, control lesions of the overlying parietal cortex, or were unoperated controls. Locomotion, measured as photocell beam breaks, was recorded during 2- or 3-h test sessions. Behavioral stereotypy was simultaneously rated. Hippocampal lesioned rats exhibited a selective enhancement in locomotion following D-amphetamine (0.0-5.6 mg/kg) when compared to animals in the control groups. Similar results were observed following injections of apomorphine (0.0-0.25 mg/kg), a mixed D1 and D2 agonist. In order to determine if D1 or D2 receptors were involved in this increased locomotion, the D1 agonist SKF 38393 (0.0-15 mg/kg) and the D2 agonist quinpirole (0.0-0.5 mg/kg) were tested alone and in combination. Hippocampal-ablated rats showed significantly increased locomotion only in response to quinpirole, suggesting that these lesion-induced increases were largely mediated by D2 receptors. When both drugs were administered together, SKF 38393 further enhanced the locomotor stimulating effects of quinpirole in hippocampal lesioned rats, indicating a synergistic interaction between D1 and D2 receptors in the modulation of locomotion. These findings provide further evidence of hippocampal modulation of locomotion and suggest that dopaminergic mechanisms in the nucleus accumbens, probably involving changes in receptor sensitivity, are involved. The results are discussed in relation to the functional roles of the nucleus accumbens and in terms of their implications for mental diseases including schizophrenia.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Apomorphine; Arousal; Brain Mapping; Dextroamphetamine; Disease Models, Animal; Dopamine Agents; Dose-Response Relationship, Drug; Ergolines; Hippocampus; Male; Motor Activity; Quinpirole; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia; Schizophrenic Psychology; Stereotyped Behavior

Prepulse inhibition of acoustic startle is deficient in schizophrenic patients and in animals injected with either direct or indirect dopamine (DA) agonists. The present experiments confirmed the hypothesis that the dopaminergic blockade of prepulse inhibition is attributable to the activation of D2 DA receptors. After systemic administrations of the D1 agonist SK&F 38393, the D2 agonist quinpirole, or a combination of the two, rats were tested for prepulse inhibition of the startle response by presenting acoustic stimuli or acoustic stimuli preceded by weak prepulses that inhibit startle. Although the D1 agonist SK&F 38393 had no effect on prepulse inhibition [0.3 to 30.0 mg/kg (1.03 to 102.82 mumols/kg)], the D agonist, quinpirole, blocked prepulse inhibition at doses of 0.3 mg/kg (1.17 mumols/kg) and 0.9 mg/kg (3.51 mumols/kg). Lower doses of quinpirole, 0.03 mg/kg (0.12 mumols/kg) and 0.1 mg/kg (0.39 mumols/kg), were ineffective. When an ineffective dose of quinpirole (0.1 mg/kg) was coadministered with 10.0 mg/kg SKF 38393, prepulse inhibition was reduced relative to saline controls. This reduction of prepulse inhibition is consistent with the synergistic effect of D1 and D2 DA receptor stimulation noted in studies of dopaminergic influences on stereotyped behavior in rats. These findings confirm that a disruption of sensorimotor gating results from D2 dopaminergic stimulation in the rat and extend the applicability of this animal model for the similar behavioral deficits exhibited by schizophrenic patients.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Acoustic Stimulation; Animals; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Ergolines; Humans; Male; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2; Reflex, Startle; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Dopamine Agents; Ergolines; Humans; Lisuride; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

To investigate the potential effect of Nicergoline, an alpha-adrenolytic drug, on negative symptoms in patients suffering from chronic schizophrenia, we administered this compound to 20 male chronic schizophrenics. Patients were previously maintained on long-term neuroleptic (NL) medication. Neuroleptic treatment was discontinued for 12 days, patients were then treated with 30 mg Nicergoline per day. Under NL (A), after 12 days NL-withdrawal (B), after 15 (C) and 30 (D) days Nicergoline treatment clinical ratings (BPRS and AMDP) and stimulation with clonidine (0.002 micrograms/kg body weight) were carried out. Norepinephrine (NE), epinephrine (E), and human growth hormone (HGH) were measured before and after application. Seventeen patients finished the study, 3 dropped out. Some ratings on the AMDP and BPRS scales showed an improvement. However, this improvement was only weak and accompanied by a worsening in other subscores. The withdrawal-induced decrease in NE serum levels continued after 15 days NIC, followed by an increase after 30 days. HGH response to clonidine stimulation was only attenuated after 30 days NIC. Epinephrine, blood pressure and heart rate showed no significant changes throughout the entire study. Our data suggest that NIC in the dosage applied shows no clear and pronounced alpha-2-adrenolytic effects and no specific clinical benefits for chronic schizophrenics. Further investigations are required to evaluate its effect on alpha-1-adrenoceptors.

Topics: Adult; Chronic Disease; Clonidine; Epinephrine; Ergolines; Growth Hormone; Humans; Male; Middle Aged; Nicergoline; Norepinephrine; Psychiatric Status Rating Scales; Schizophrenia

Topics: Aged; Bromocriptine; Cognition Disorders; Confusion; Dose-Response Relationship, Drug; Electroencephalography; Ergolines; Female; Humans; Male; Mental Disorders; Middle Aged; Parkinson Disease; Personality Disorders; Psychoses, Substance-Induced; Schizophrenia

Topics: Animals; Bromocriptine; Cyclic AMP; Ergolines; Female; Humans; Huntington Disease; Male; Middle Aged; Motor Activity; Nervous System Diseases; Parkinson Disease; Rats; Schizophrenia; Stereotyped Behavior; Synapses