ceruletide and Schizophrenia

It has been suggested that cholecystokinin (CCK), a gut-brain peptide found in high concentrations in the mammalian brain, might be implicated in the neurobiology of anxiety and panic disorder. The administration of CCK tetrapeptide induced panic attacks analogous to spontaneous ones in patients suffering from panic disorder and to a lesser degree in healthy volunteers. In animal models of anxiety, the pretreatment with CCK agonists and antagonists produced, respectively, anxiogenic- and anxiolytic-like action on the exploratory paradigms. On the other hand, CCK could also play a role in the pathophysiology of schizophrenia. The administration of CCK agonists (caerulein, CCK-8s) to rodents results in behavioural effects analogous to those of antipsychotic drugs. However, CCK agonists lack any activity in rodent behavioural models to reveal antipsychotic drugs. A significant reduction of CCK concentration and CCK receptors has been shown in cortical and limbic structures of patients suffering from schizophrenia. Nevertheless, administration of CCK agonists to these patients does not effect their symptoms. Two major conclusions should be drawn: first, CCK is involved in the neurobiology of anxiety; second, changes in the CCK system in schizophrenia could be linked to a cortical neurodegeneration related to this disease.

Topics: Animals; Anxiety Disorders; Ceruletide; Cholecystokinin; Humans; Neurotransmitter Agents; Receptors, Cholecystokinin; Schizophrenia; Sincalide

Topics: Ceruletide; Humans; Schizophrenia

CCK-IR is co-localized with DA in some DA neurons projecting to limbic structures. The extent of the co-localization is species dependent. The co-localization of CCK and DA is of interest in view of the DA hypothesis of schizophrenia and the putative role of limbic dysfunction in the pathophysiology of this disorder. In animals biochemical, electrophysiological and behavioural studies point to an interaction between CCK and DA. Whereas some investigations point to an inhibitory effect on DA function, which would be compatible with a potential antischizophrenic action, others point to an enhancement or no effect. CCK peptides show a neuroleptic-like profile in several screening tests for neuroleptics but not in all studies. In man there is endocrinological evidence for an inhibitory effect of CCK-33 and CCK-8 on DA function. However, alternate explanations are possible. CSF CCK-IR is unchanged or decreased in schizophrenia. Autopsy investigations have shown significant decreases, increases or no change in brain CCK-IR concentrations and a decrease in CCK-33 binding in schizophrenia. Eight of 11 clinical trials with CER, CCK-8 or CCK-33 have shown a therapeutic effect in schizophrenia; only two of these eight trials have been double-blind studies. The three controlled investigations which have shown no effect have used only small patient populations. None of the trials have used an active placebo. It is difficult to reconcile the apparent long duration of antipsychotic activity with the short half-life of the peptides and problems of the peptides in crossing the blood brain barrier. Despite these apparent anomalies information to date is sufficiently impressive to warrant further detailed investigation of CCK-DA-interactions and the evaluation of the clinical effects of a variety of CCK peptides and related compounds, natural and synthetic, which may more easily cross the blood brain barrier and which may show regional selectivity in site of action in brain.

Topics: Antipsychotic Agents; Ceruletide; Cholecystokinin; Dopamine; Humans; Neurotransmitter Agents; Receptors, Dopamine; Schizophrenia; Sincalide

The effectiveness of a once-weekly i.m. injection of ceruletide (0.8 microgram/kg) in suppressing the symptoms of neuroleptic-induced tardive dyskinesia (TD) was evaluated in a double-blind, placebo-controlled, matched-pairs study. Global evaluation of the severity of TD symptoms over the 8-week study period revealed a significant improvement with ceruletide as compared with placebo. Analysis of the therapeutic response to ceruletide over the course of treatment revealed a slow, but long-lasting improvement of TD symptoms. Side effects, which were mild and transient, consisted mainly of nausea and epigastric discomfort. The incidence of side effects did not differ between the ceruletide- and placebo-treated groups. Ceruletide appears to be a novel and practical treatment that can substantially alleviate the symptoms of dyskinesia.

Topics: Adult; Aged; Antipsychotic Agents; Ceruletide; Double-Blind Method; Dyskinesia, Drug-Induced; Female; Humans; Male; Matched-Pair Analysis; Middle Aged; Neurologic Examination; Schizophrenia; Schizophrenic Psychology

1. The efficacy of ceruletide as a supplement in treating schizophrenics was tested by monitoring the Brief Psychiatric Rating Scale (BPRS) and the EEG. 2. Eight male inpatients with schizophrenia were administered fixed doses of neuroleptics during the study. 3. A control EEG recording and BPRS scoring were done before ceruletide administration. 4. Doses of 0.8 micrograms/kg/week of ceruletide and of placebo were given intramuscularly in a double-blind, crossover design for 3 consecutive weeks, and no treatment followed for 1 week. 5. EEG recordings and BPRS scoring were carried out once weekly. There were no significant differences in the total BPRS scores or the scores of each item between ceruletide and placebo. 6. With ceruletide treatment, the power values of the frontal EEGs increased in the whole bands but only in the first week. 7. The EEG values in the occipital area increased in alpha and beta activities slightly in the third week and markedly in the fourth week. 8. The power values in the right temporal area decreased in fast beta activity in the second and third weeks but increased in alpha activity in the third and fourth week. 9. The power of the left temporal area increased in both alpha and beta bands in the second week, and this continued to the fourth week. 10. These results suggest that treatment with ceruletide might fail to improve the symptoms of schizophrenics but does affect their EEGs, and that ceruletide may have a delayed effect.

Topics: Adult; Cerebral Cortex; Ceruletide; Electroencephalography; Evoked Potentials; Humans; Injections, Intramuscular; Male; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Ceruletide; Clinical Trials as Topic; Double-Blind Method; Humans; Random Allocation; Schizophrenia

The neuropeptides desenkephalin-gamma-endorphin (DE gamma E) and ceruletide were administered intramuscularly to patients with schizophrenic psychoses following a double-blind placebo-controlled design, including a total of 44 subjects. Neuroleptic medication was continued during the experimental period, which was started with one placebo injection for all patients. One week later subjects received a single intramuscular injection with 3 mg DE gamma E, 40 micrograms ceruletide or placebo. After an interval of 10 days, the patients received six similar injections over a period of 2 weeks. Treatment with either peptides resulted in a decrease of psychotic symptomatology as compared to placebo treatment. The beneficial effect of the peptides lasted at least 2 weeks after the experimental treatment period. Of the 14 patients treated with placebo only, three showed a slight response. Of the 30 patients treated with the neuropeptides, eight did not respond (DE gamma E: 3; ceruletide: 5), eight had a slight response (DE gamma E: 6; ceruletide: 2) and 14 responded moderately or markedly (DE gamma E: 6; ceruletide: 8). No obvious difference between the effects of the two neuropeptides was found, besides a somewhat earlier onset of the effect of ceruletide. Patients presenting relatively less negative psychotic symptoms were particularly susceptible to treatment with either peptide. Apart from slight and short-lasting gastrointestinal complaints after the first injections with ceruletide in some patients, no side effects were observed.

Topics: Adult; beta-Endorphin; Ceruletide; Clinical Trials as Topic; Double-Blind Method; Endorphins; Gastrointestinal Diseases; Humans; Injections, Intramuscular; Schizophrenia

We evaluated ceruletide, a cholecystokininlike peptide, in a double-blind, placebo-controlled study of 20 male chronic schizophrenic patients. After baseline investigations, 10 patients received 0.3 microgram/kg body weight ceruletide, and 10 patients received placebo (normal saline) intramuscularly once weekly for 3 consecutive weeks. Psychopathology was rated on the Brief Psychiatric Rating Scale and the Nurses' Observation Scale for Inpatient Evaluation. Blood was drawn on the same days for estimation of norepinephrine, epinephrine, beta-endorphin, cortisol, and prolactin. There were no significant changes in biochemical parameters. With regard to psychopathology, no significant differences in behavioral ratings were found between the ceruletide- and placebo-treated groups. Furthermore, there was no changes in either positive or negative symptoms of schizophrenia secondary to ceruletide. Contrary to uncontrolled studies, we failed to show antipsychotic properties of ceruletide.

Topics: Adult; Ceruletide; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Humans; Male; Middle Aged; Psychopathology; Schizophrenia

Ceruletide, an analog of cholecystokinin (CCK), has been reported to have neuroleptic-like activity in mice, and, in three open studies, to benefit schizophrenic patients. This study evaluated ceruletide in schizophrenia using a double-blind design. Subjects were 17 chronic schizophrenics with residual symptoms following stabilization with neuroleptics. Patients randomly received two injections, 1 week apart, of either ceruletide (0.6 microgram/kg im) or placebo, while continuing neuroleptics; this regimen was found helpful in earlier studies. Evaluation included ratings of 29 variables related to prognosis in schizophrenia (e.g., age, number of previous hospitalizations), regular BPRSs and SCL-90s, and psychiatrist, patient, and relative ratings of global improvement. Results showed few significant differences between ceruletide and placebo, with exceptions as likely to favor placebo as ceruletide. Among the patients on ceruletide, no predictors of benefit were found. Possible reasons for the negative results are discussed.

Topics: Antipsychotic Agents; Ceruletide; Chronic Disease; Double-Blind Method; Humans; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Aged; Ceruletide; Cholecystokinin; Clinical Trials as Topic; Dopamine; Double-Blind Method; Female; Humans; Male; Middle Aged; Parkinson Disease; Schizophrenia

Eight neuroleptic-resistant schizophrenic patients were treated with ceruletide, a cholecystokinin-like peptide, in a placebo-controlled, double-blind, crossover study. Ceruletide or placebo was administered intramuscularly twice a day for 4 consecutive days while patients were maintained on a constant dose of fluphenazine. There were no changes in either the positive or negative symptoms of schizophrenia between the periods of placebo and ceruletide administration. To further characterize ceruletide actions we also administered it to seven normal volunteers and evaluated its effects on cognition and mood. Volunteers were administered ceruletide (0.3 micrograms/kg or 0.6 micrograms/kg) or saline placebo intramuscularly. Ceruletide had no effects on recent or remote memory or attention, but the higher dose did cause a significant increase in fatigue. These results suggest that although CCK-like peptides lack antipsychotic or cognitive effects they do induce mild sedation. This sedation may be part of a "satiety-like" state induced by peripheral administration of CCK.

Topics: Adult; Ceruletide; Cholecystokinin; Clinical Trials as Topic; Cognition; Emotions; Female; Humans; Male; Receptors, Dopamine; Schizophrenia

Topics: Animals; Ceruletide; Cholecystokinin; Clinical Trials as Topic; Feeding Behavior; Humans; Motor Activity; Parkinson Disease; Receptors, Dopamine; Schizophrenia; Sincalide; Synapses

Cholecystokinin (CCK) has been implicated as a neurotransmitter, and recent research has identified CCK as having potential antipsychotic effects in patients with chronic schizophrenia. Nine chronic schizophrenic patients with prominent psychotic symptoms and a history of resistance to conventional neuroleptic treatment were administered ceruletide, a synthetic decapeptide of cerulein, intramuscularly. No clinically significant short-term or long-term therapeutic effects were demonstrated, despite the results of statistical analysis which indicated significant improvement. The implications of this open clinical trial for a new treatment modality of chronic schizophrenia are discussed.

Topics: Adult; Ceruletide; Cholecystokinin; Clinical Trials as Topic; Double-Blind Method; Humans; Injections, Intramuscular; Male; Middle Aged; Schizophrenia

Ceruletide, a cholecystokinin analogue, has been reported to interact with dopamine in the CNS and to benefit schizophrenic individuals. The authors, using a double-blind design, a higher total dose, and a larger sample size than previous studies, found no evidence of benefit.

Topics: Adult; Ceruletide; Clinical Trials as Topic; Double-Blind Method; Humans; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Ceruletide; Cholecystokinin; Chronic Disease; Clinical Trials as Topic; Female; Humans; Long-Term Care; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia

Peptides related to the C-terminal part of cholecystokinin, including ceruletide, were found to be active in a number of behavioral test procedures in rats, predicting antipsychotic action. In a subsequent clinical trial ceruletide was administered intramuscularly in a dose of 40 micrograms twice for 2 consecutive weeks to 6 neuroleptic-treated schizophrenic patients following a single-blind design. In 3 patients, a pronounced long-lasting antipsychotic effect was observed, while in the other 3 the response was less marked. It is suggested that ceruletide may be a potential antipsychotic peptide.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Brief Psychiatric Rating Scale; Ceruletide; Drug Evaluation; Drug Evaluation, Preclinical; Humans; Male; Rats; Rats, Inbred Strains; Schizophrenia

Eight neuroleptic-resistant schizophrenic patients were treated with ceruletide diethylamine, a cholecystokininlike peptide, in a placebo-controlled, double-blind, cross-over study. Ceruletide or placebo was administered intramuscularly twice a day for four consecutive days while patients received a constant dose of fluphenazine hydrochloride. Cholecystokinin octapeptide was also administered to four different schizophrenic patients in a double-blind, cross-over study. Cholecystokinin or placebo was administered as a slow intravenous infusion daily for four days. There were no changes in either the positive or negative symptoms of schizophrenia between the periods of placebo, ceruletide, or cholecystokinin administration. Furthermore, there was no tendency for the patients' conditions to either improve or worsen during the course of ceruletide or cholecystokinin treatment. In contrast to previous reports from uncontrolled studies, cholecystokininlike peptides appear to be devoid of antipsychotic properties when administered parenterally.

Topics: Adult; Ceruletide; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Sincalide

Topics: Ceruletide; Chronic Disease; Clinical Trials as Topic; Humans; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Adult; Ceruletide; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Adolescent; Adult; Antipsychotic Agents; Ceruletide; Clinical Trials as Topic; Humans; Middle Aged; Schizophrenia

Topics: Adult; Ceruletide; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia

Topics: Ceruletide; Chronic Disease; Clinical Trials as Topic; Humans; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

1. One schizophrenic patient with drug-induced tardive dystonia was treated with ceruletide. 2. After the injection, dystonia showed a tendency toward rapid amelioration in 3 days; meanwhile, however, mental manifestations became exacerbated within 3 weeks. 3. We discuss some aspects of the effects of ceruletide.

Topics: Adult; Ceruletide; Dyskinesia, Drug-Induced; Electroconvulsive Therapy; Humans; Male; Prolactin; Psychiatric Status Rating Scales; Schizophrenia

1. Seven patients with TD were treated with a single dose of ceruletide 0.8 microgram/kg i.m. 2. EMG and MV were recorded, and the average power spectrum was computed. 3. Effect of ceruletide on TD within 2 hr after injection was varied (3 cases: inhibitory, 2 cases: facilitatory, 2 cases: no effect). 4. Two patients with severe TD, who showed improvement after a single administration, received repeated administration of ceruletide (0.6 microgram/kg i.m.) and their TD symptoms were recorded on videotape for blind consensus ratings. In both patients ceruletide caused a marked decrease in severity of TD, and the effects lasted for several weeks. 5. The present findings might contribute to further understanding of the role of CCK in the brain and to the treatment of TD.

Topics: Adult; Antipsychotic Agents; Ceruletide; Dyskinesia, Drug-Induced; Electromyography; Female; Humans; Male; Middle Aged; Schizophrenia

To define the characteristics of chronic schizophrenic patients who had responded poorly to treatment with ceruletide, several neuroendocrinological tests were carried out in 5 responders and 5 non-responders. Both thyroid-stimulating hormone and prolactin responses to thyrotropin-releasing hormone stimulation were within normal ranges in all subjects. The luteinizing hormone response to luteinizing hormone-releasing hormone, was slightly weaker in non-responders. There were no differences in the insulin tolerance test between responders and non-responders. Unusually delayed or prolonged growth hormone response to arginine infusion was observed in non-responders. These findings suggest dysfunction of the hypothalamo-pituitary system, especially of the arcuate nucleus and its functionally related areas, in non-responders.

Topics: Antipsychotic Agents; Ceruletide; Chronic Disease; Drug Resistance; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Insulin; Male; Neurosecretory Systems; Schizophrenia; Thyrotropin-Releasing Hormone

Neuroleptic-free schizophrenic patients received caerulein, a potent analogue of cholecystokinin octapeptide, in a fixed- and rising-dose schedule. In addition, neuroleptic-treated patients received a single dose of the peptide with a 4-week follow-up. No significant change in mental status was observed after any of these administration schedules. Peak plasma levels of caerulein were noted at 20-30 min after IM administration; at this time no changes in cortical evoked potential were demonstrated. Furthermore, levels of cholecystokinin were not found to be reduced, but were in fact elevated in lumbar cerebrospinal fluid of schizophrenic patients. These data argue against the antipsychotic efficacy of systemic caerulein administration and, because evidence of CNS response to CCK is lacking, suggest that other pharmacologic strategies may be necessary to effectively modify central peptide systems with systemically administered drugs.

Topics: Adult; Ceruletide; Cholecystokinin; Evoked Potentials; Humans; Male; Neurons; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Seven patients with bucco-lingual dyskinesia were treated with a single dose of ceruletide 0.8 micrograms/kg IM, a potent analogue of cholecystokinin octapeptide. Time-course effects of the drug were then followed up to 6 weeks after injection in the longest case. To assess changes in severity of dyskinesia objectively, electromyogram and microvibration were recorded. These data were subjected to the Fast Fourier Transform and an averaged power spectrum was computed. The effect of ceruletide on dyskinesia within 2 h after injection differed (three cases: inhibitory, two cases: facilitatory, two cases: no effect). It was notable that a long-lasting inhibitory effect of this peptide was observed in two severe irreversible cases. The present findings might contribute to further understanding of the physiopathophysiological role of cholecystokinin-like peptides in the brain and to practical treatment of tardive dyskinesia.

Topics: Adult; Aged; Ceruletide; Dyskinesia, Drug-Induced; Electromyography; Female; Humans; Male; Middle Aged; Pilot Projects; Schizophrenia

Topics: Adult; Antipsychotic Agents; Ceruletide; Chronic Disease; Drug Evaluation; Female; Humans; Male; Middle Aged; Schizophrenia

Topics: Animals; Apomorphine; Behavior, Animal; Brain; Bucladesine; Ceruletide; Cholecystokinin; Chronic Disease; Dopamine; Humans; Rats; Rats, Inbred Strains; Schizophrenia; Species Specificity

Topics: Ceruletide; Eye Movements; Humans; Schizophrenia

Caerulein, a decapeptide chemically related to CCK-8, was administered intramuscularly to 20 patients with chronic schizophrenia in two different doses of 0.3 and 0.6 microgram/kg. BPRS ratings were made before and 3 weeks after the injection. The neuroleptic therapy was not discontinued, but both drug and dose were not changed at least 3 weeks before the first injection and during the study period. Clinically obvious and statistically significant improvement in psychotic symptoms occurred shortly after the injection of caerulein. The greatest change occurred 1--2 weeks later. There was an evident correlation between the observed changes and the dose injected. Our findings suggest that caerulein has a long-acting, antipsychotic activity in chronic schizophrenia. Furthermore, our findings suggest the involvement of CCK-like peptides in the pathogenesis of schizophrenia.

Topics: Adult; Ceruletide; Chronic Disease; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology