gamma-endorphin--des-tyr(1)- and Schizophrenia

(Des-Tyr)-gamma-endorphin is a naturally-occurring neuropeptide. It has no opiate-like activity, and animal research suggests that it shares with haloperidol certain effects on animal behaviour. The compound was given to schizophrenics, and initial claims of 'a reduction or total disappearance of symptoms in schizophrenics partly or completely resistant to conventional neuroleptics and suffering from long-lasting psychoses' were made. Several investigators have attempted to replicate these findings without success. This paper reviews the shortcomings in methodology and interpretation of results of the investigations carried out so far and emphasises that the fundamental question of whether (Des-Tyr)-gamma-endorphin has any clinical antipsychotic effect has not been answered by any study to date.

Topics: Antipsychotic Agents; Endorphins; Humans; Peptide Fragments; Psychotic Disorders; Schizophrenia

The biological enigma of schizophrenia has led, on the basis of thin evidence, to widen the field of clinical research to a study of endomorphines in this disease. Too many different methods of measuring the levels of opiate peptides in the CSF have been used so that it is not possible to analyse the results statistically. Clinical trials of agonists and antagonists to the opiate receptors have once again emphasised the biochemical heterogeneity of schizophrenics but have not allowed any confirmation that the endorphinical system plays any part in the genesis or symptomatology of schizophrenia. The presence of sub-groups who respond positively to experimental treatment can lead to the hope, despite the uncertainties of their mode of pharmacological action, to the next advance in the routine treatment of schizophrenia.

Topics: beta-Endorphin; Clinical Trials as Topic; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Endorphins; Humans; Naloxone; Peptide Fragments; Receptors, Opioid; Schizophrenia

Clinical prospects of an analog of thyrotropin-releasing hormone (DN-1417) and des-tyrosine-gamma-endorphin (DT gamma E) in schizophrenia were examined by using the Brief Psychiatric Rating Scale (BPRS) and the electroencephalogram (EEG). Twelve inpatients with chronic schizophrenia were administered fixed doses of neuroleptics throughout the study. Six patients were treated with DN-1417 (DN-1417 group), and the remaining 6 patients with DT gamma E (DY gamma E group). One mg/day of DN-1417 or DT gamma E was given intramuscularly for 2 consecutive weeks followed by 1 week of no drug treatment. In the DN-1417 group, both total BPRS scores and scores on hallucinatory behaviour and unusual thought content decreased in the first and third weeks. The power values of alpha and beta activities from the frontal area increased in the first and third weeks, whereas an increase in alpha activity and a decrease of high-fast beta activity from the occipital area were obtained during the study. On the other hand, the DT gamma E group failed to show either a decrease in BPRS scores or any remarkable EEG changes except for a slight decrease in beta activity. These results suggest that the positive symptoms of schizophrenia are improved by DN-1417 treatment, and that the alterations in BPRS scores coincide with changes in the frontal EEG.

Topics: Adult; Antidepressive Agents; Antipsychotic Agents; Clinical Trials as Topic; Electroencephalography; Endorphins; Female; Humans; Male; Middle Aged; Peptide Fragments; Psychiatric Status Rating Scales; Schizophrenia; Thyrotropin-Releasing Hormone

Des-tyr1-gamma-endorphin (DT gamma E) was administered intramuscularly in a dose of 1 mg/day for 10 days to 18 neuroleptic-free schizophrenic patients in a double-blind crossover design. Six patients showed either a slight or no antipsychotic response; seven patients showed a moderate antipsychotic response; and the remaining five patients showed a marked antipsychotic response. DT gamma E led to a decrease of plasma prolactin levels in patients treated with DT gamma E in the first period of experimental treatment as compared to those treated with placebo. Neither plasma levels of growth hormone and cortisol nor cerebrospinal fluid concentrations of homovanillic acid, 5-hydroxyindoleacetic acid, and 3-methoxy-4-hydroxyphenylglycol were affected by DT gamma E. Patients suffering from a hebephrenic or paranoid type of schizophrenia and those presenting relatively fewer negative symptoms were most susceptible to treatment with DT gamma E. These data confirm and extend previous findings that DT gamma E has antipsychotic properties in a number of schizophrenic patients.

Topics: Adolescent; Adult; Clinical Trials as Topic; Double-Blind Method; Endorphins; Female; Growth Hormone; Homovanillic Acid; Humans; Hydrocortisone; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Peptide Fragments; Prolactin; Schizophrenia; Schizophrenia, Disorganized; Schizophrenia, Paranoid

Des-tyrosine-gamma-endorphin (DT gamma E) has been reported to alleviate symptoms of schizophrenia. Attempting to replicate those reports, we administered 1 mg of DT gamma E, i.m., for 8 consecutive days to nine patients meeting the DSM-III criteria for schizophrenia. Patients in this double-blind, crossover, and placebo-controlled study showed a statistically significant, but clinically modest improvement. The improvement was detectable during the first several days of the DT gamma E treatment; the symptoms then returned to baseline level in spite of continued doses of DT gamma E. Testing the metabolism of DT gamma E in the patients' plasma, we found a high rate of formation and of degradation, but the metabolic rates were not related to clinical symptoms.

Topics: Adult; Endorphins; Humans; Male; Metabolic Clearance Rate; Peptide Fragments; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Destyrosine-gamma-endorphin (DTGE) has purported neuroleptic properties, although the findings have been conflicting. Four chronic psychotic inpatients with neuroleptic-induced dyskinesias were treated with single injections of placebo and DTGE in high doses (20-120 mg). No consistent differences were found in tardive dyskinesia, parkinsonism, eye-blinking rates, or mental status. Laboratory tests were unchanged. It is concluded that acute DTGE treatment has no beneficial effect in drug-induced dyskinesia.

Topics: Adult; Aged; Antipsychotic Agents; Blinking; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Endorphins; Humans; Male; Middle Aged; Parkinson Disease, Secondary; Peptide Fragments; Receptors, Dopamine; Schizophrenia; Schizophrenic Psychology

The pharmacological actions of gamma-type endorphins show similarities to those of the neuroleptics. Two fragments of gamma-endorphin (beta-LPH 61-77) were therefore tested in patients with schizophrenic and schizo-affective psychoses who had shown an insufficient response to neuroleptics. The fragments were DT gamma E (beta-LPH 62-77) and DE gamma E (beta-LPH 66-77). Some of the patients studied responded favorably to this treatment. A number of criteria of differentiation between responders and nonresponders are discussed. The influence of DT gamma E on the central DA metabolism differs from that of the neuroleptics. It is therefore conceivable that gamma-type endorphins represent a different principle of action. The therapeutic efficacy of these compounds lends support to the hypothesis that disorders of central endorphin metabolism may play a role in the pathogenesis of psychoses of the schizophrenic type.

Topics: beta-Endorphin; Brain; Clinical Trials as Topic; Dopamine; Double-Blind Method; Endorphins; gamma-Endorphin; Humans; Peptide Fragments; Psychotic Disorders; Receptors, Dopamine; Schizophrenia; Schizophrenic Psychology

Topics: Adult; beta-Endorphin; Brain; Clinical Trials as Topic; Dopamine; Double-Blind Method; Endorphins; Female; gamma-Endorphin; Humans; Male; Middle Aged; Peptide Fragments; Schizophrenia

Topics: Clinical Trials as Topic; Endorphins; Humans; Peptide Fragments; Schizophrenia

Topics: Alzheimer Disease; Clinical Trials as Topic; Endorphins; Humans; Lypressin; Mental Disorders; Peptide Fragments; Peptides; Schizophrenia

Topics: Brief Psychiatric Rating Scale; Double-Blind Method; Drug Evaluation; Endorphins; gamma-Endorphin; Humans; Peptide Fragments; Psychotic Disorders; Schizophrenia

The endorphin neuropeptides may have neuroleptic-like effects on dopamine function and may be antischizophrenic. Ten chronic psychotic patients with neuroleptic-induced tardive dyskinesia and parkinsonism received placebo and des-tyrosine-gamma-endorphin (DT gamma E). Drug effects on movement disorders and eye-blinking rates were assessed by blind evaluations of randomly sequenced videotapes made during standardized examinations before and 30, 60, and 120 minutes after each injection and at 24 hours postinjection on days of consecutive treatment. Changes in schizophrenic symptoms were evaluated openly with the schizophrenia subscale of the Comprehensive Psychiatric Rating Scale. There were no significant effects of DT gamma E on any parameter and no side effects. This suggests that DT gamma E, within the tested dose range, does not influence the pathophysiology of neuroleptic-induced dyskinesias or chronic schizophrenia or have neuroleptic properties. However, DT gamma E is well tolerated and should be tested with higher doses during prolonged treatment.

Topics: Blinking; Clinical Trials as Topic; Double-Blind Method; Dyskinesia, Drug-Induced; Endorphins; Female; Humans; Male; Parkinson Disease, Secondary; Peptide Fragments; Placebos; Receptors, Dopamine; Schizophrenia

The neuropeptide (des-tyrosine1)-gamma-endorphin (DT gamma E; beta-LPH 62-77) was given to 10 schizophrenic patients who had been free of neuroleptic medication for at least 3 weeks. DT gamma E was injected intramuscularly in a dose of 1 mg daily for 10 days following a double-blind placebo-controlled crossover design. In 4 of the 10 patients a pronounced antipsychotic effect was observed; in 3 a temporary or slight reduction of psychotic symptoms occurred; and in 3 no response was noted. DT gamma E led to decreased plasma levels of prolactin and in some patients to increased concentrations of homovanillic acid in cerebrospinal fluid (CSF). Neither plasma levels of growth hormone and cortisol nor CSF concentrations of 5-hydroxyindoleacetic acid were affected by DT gamma E. These data confirm that DT gamma E has antipsychotic properties in a number of schizophrenic patients and suggest an interaction between DT gamma E and central dopaminergic systems.

Topics: Adult; Clinical Trials as Topic; Double-Blind Method; Endorphins; Female; Growth Hormone; Humans; Hydrocortisone; Male; Peptide Fragments; Prolactin; Psychotic Disorders; Schizophrenia; Schizophrenia, Catatonic; Schizophrenia, Paranoid; Schizophrenic Psychology

Topics: Endorphins; Humans; Peptide Fragments; Schizophrenia

A double-blind placebo-controlled cross-over investigation of the possible antipsychotic action of [des-Tyr1]-gamma-endorphin (DT gamma E) was undertaken in schizophrenic patients. This non-opiod derivative of gamma-endorphin has recently been shown to exert both neuroleptic-like effects in animals and an antipsychotic action in schizophrenic patients failing to respond to conventional neuroleptic therapy. 13 patients undergoing continuous neuroleptic therapy, and suffering from either chronic or acute, frequently-relapsing schizophrenia and displaying persistent productive symptoms (hallucinations, acute delusions) were selected for the trial. After one day of single-blind injection of placebo, two successive double-blind treatment periods of 4 days each followed, viz 4 days with i.m. injections of 2 mg DT gamma E preceding 4 days of placebo injections or vice versa. Psychopathological evaluation was performed twice daily by use of the IMPS and an eight-point-scale appropriate for the estimation of special target symptoms (VBS). The mean data obtained from the whole sample of 13 patients show that placebo and DT gamma E produce a reduction in symptomatology of an appoximately equal magnitude. The results provide no support for the hypothesis of an antipsychotic efficacy of DT gamma E in the treatment of chronic schizophrenic patients. In the subgroup of acute cases, however, a therapeutic action of DT gamma E appears possible

Topics: Adult; Clinical Trials as Topic; Double-Blind Method; Endorphins; Female; Humans; Injections, Intramuscular; Male; Middle Aged; Peptide Fragments; Psychiatric Status Rating Scales; Schizophrenia

It was postulated from animal experiments that gamma-endorphin and, in particular, the nonopiate-like peptide [des-Tyr1]-gamma-endorphin (DTgammaE, beta-lipotropin [beta-LPH]62-77) have neurolepic-like activity. To test this, 14 patients with long-lasting, relapsing schizophrenic or schizoaffective psychosis resistant to conventional neuroleptics were treated with DTgammaE. An open design was used first for six patients (study 1) and a double-blind, crossover design for the other eight (study 2). In study 1, all neuroleptic medication was discontinued and 1 mg of DTgammaE zinc phosphate was given daily intramuscularly for about seven days. In study 2, six patients were maintained with neuroleptic therapy and two patients were drug free; all eight received daily intramuscular injections of 1 mg of nonlasting DTgammaE in saline and solution for eight days. There was transient or semipermanent improvement in both studies in which the psychotic symptoms diminished or even disappeared. In study 2, there was a slight but significant improvement with the first treatment. Improvement continued and by day 4, the psychotic symptoms had almost disappeared. No toxic side effects were noted. These effects of DTgammaE may be a consequence of the normalization of beta-endorphin homeostasis in the brain.

Topics: Adult; Aggression; Clinical Trials as Topic; Double-Blind Method; Endorphins; Female; Hallucinations; Humans; Male; Middle Aged; Motor Activity; Peptide Fragments; Schizophrenia; Schizophrenia, Catatonic

A review of treatment trials with DT gamma E revealed widely discrepant results. Relevant variables were the variety of measures employed for monitoring psychotic symptoms, and the different criteria used to judge the degree of improvement. The authors suggest a uniform outcome criterion for early trials of new treatments, which would generate more consistent and comparable results between studies, and give a stronger indication of the value of the treatment under test. When the data from the various treatment trials of DT gamma E were reanalysed, applying a uniform outcome criterion of improvement of a change of 80% or more on rating-scale score, the results were more consistent than would have been suspected from the original reports.

Topics: Clinical Trials as Topic; Endorphins; Humans; Peptide Fragments; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

In the past decade both basic and clinical research on endogenous opiates has involved many aspects of medicine. This review focuses on the clinical literature that relates physiology and pathophysiology of the endogenous opiates to schizophrenia. Three major investigative approaches are described and their results evaluated. These approaches are described and their results evaluated. These approaches include assays of endogenous opiates in the context of clinical illness and use of exogenous opiates as well as exogenous opiate antagonists in the treatment of clinical illness. Current understanding at both the basic science and clinical research levels does not allow firm conclusions about the role of endogenous opiates in schizophrenia; however, the evolution of the growing understanding is used by the author to provide a speculative hypothesis.

Topics: Animals; Antipsychotic Agents; beta-Endorphin; Double-Blind Method; Drug Therapy, Combination; Endorphins; Humans; Peptide Fragments; Rats; Schizophrenia; Schizophrenic Psychology

Des-tyrosine-gamma-endorphin (DT gamma E), a derivative of gamma-endorphin, which has been reported to have some neuroleptic-like properties in man, was administered to eight hospitalized schizophrenic patients (six chronic, one subacute, one acute) in an open study. Following an initial drug-free period, patients were given DT gamma E for 12 days in doses ranging from 1 to 10 mg/day. Two of the patients were markedly improved after receiving DT gamma E. The improvement was sustained for 2 months in one subjects, while the other deteriorated to pretreatment status within 48 hours of the discontinuation of DT gamma E. Of the other six patients, one showed moderate improvement, three showed minimal improvement, and two showed no change. Improvement was mainly in the area of social functioning; change in positive psychotic symptoms was less noticeable. The positive results obtained in this study in some subjects could have been nonspecific effects, rather than pharmacological action, since social functioning, the main area of improvement, may be especially sensitive to expectancy effects in open trials. Nevertheless, further study of DT gamma E in acute schizophrenics for longer periods appears indicated.

Topics: Adult; Antipsychotic Agents; Dose-Response Relationship, Drug; Endorphins; Female; Humans; Male; Peptide Fragments; Pilot Projects; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

In order to investigate whether genetic factors are involved in the response of schizophrenic patients to treatment with gamma-type endorphins, we typed 32 Dutch schizophrenic patients for the HLA-A, -B, -C and -DR antigens. The total patient group showed an increase of HLA-Bw4 and HLA-Cw1. A subgroup of 20 paranoid patients showed an increase of HLA-Cw1 and a significant heterogeneity for the HLA-C locus. In 16 patients who responded moderately or markedly to treatment with gamma-type endorphins, an increase of HLA-B15/Cw3 and a decrease of HLA-B17 were found as compared to 16 patients with no or a slight response. Moreover, HLA-B15 was particularly increased in those patients who responded markedly and remained free of psychotic symptoms for a period of at least 6 months after treatment with gamma-type endorphins (RR = 24.6, Puncorr. = 0.0015). Our results suggest that genetic factors coded for within the HLA region are associated with paranoid schizophrenia, and that HLA-B15/Cw3 is associated with a marked and prolonged response to treatment with gamma-type endorphins.

Topics: beta-Endorphin; Endorphins; gamma-Endorphin; HLA Antigens; HLA-B Antigens; HLA-B15 Antigen; HLA-C Antigens; Humans; Peptide Fragments; Schizophrenia

Topics: Adult; Endorphins; Female; H-Reflex; Humans; Male; Peptide Fragments; Pilot Projects; Schizophrenia

Topics: Adolescent; Adult; Antipsychotic Agents; Endorphins; Female; H-Reflex; Humans; Male; Peptide Fragments; Reflex, Monosynaptic; Schizophrenia; Time Factors

Topics: Acute Disease; Adult; Antipsychotic Agents; Chronic Disease; Drug Evaluation; Endorphins; Female; Humans; Male; Peptide Fragments; Psychiatric Status Rating Scales; Schizophrenia

Topics: Animals; Antipsychotic Agents; Behavior, Animal; beta-Endorphin; Dopamine; Double-Blind Method; Endorphins; gamma-Endorphin; Humans; Peptide Fragments; Psychiatric Status Rating Scales; Psychotic Disorders; Rats; Receptors, Dopamine; Receptors, Opioid; Schizophrenia; Schizophrenic Psychology

The beta-lipotrophin fragment des-tyrosine-gamma-endorphin (DT gamma E) has been reported to have antipsychotic properties. We administered the compound without other psychoactive drugs to a subpopulation of schizophrenic subjects. Male patients with chronic psychotic illness and previous long-term neuroleptic therapy were given DT gamma E at a similar dose and duration of treatment that have been reported to be effective. No improvement in psychotic symptoms occurred; plasma prolactin level, a parameter characteristically altered by neuroleptic treatment, did not change. The beneficial effects of DT gamma E in schizophrenia may be specific to a diagnostic category, may be dependent on past pharmacologic treatment, or may occur only in combination with other drugs.

Topics: Chronic Disease; Drug Evaluation; Endorphins; Humans; Injections, Intramuscular; Male; Peptide Fragments; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Animals; Dose-Response Relationship, Drug; Double-Blind Method; Endorphins; Humans; Peptide Fragments; Psychiatric Status Rating Scales; Rats; Receptors, Dopamine; Schizophrenia; Schizophrenic Psychology

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Brain; Endorphins; Humans; Mice; Peptide Fragments; Rats; Receptors, Drug; Receptors, Opioid; Schizophrenia; Spiperone

Topics: Adult; Antipsychotic Agents; Chronic Disease; Endorphins; Female; Humans; Injections, Intramuscular; Male; Peptide Fragments; Placebos; Schizophrenia