Itsuyuki Koga

Biphasic and long-lasting effect of ceruletide on tardive dyskinesia.

A 55-year-old schizophrenic inpatient with buccolingual dyskinesia was treated with a single dose of ceruletide 0.8 μg/kg IM. Time-course effects of the drug were then followed for up to 6 weeks after injection. To assess changes in severity of bucco-lingual dyskinesia objectively, electromyogram (EMG) and microvibration (MV) were recorded. Simultaneously, bucco-lingual dyskinesias were also evaluated by using a five-point rating scale. Before injection of ceruletide, severity of dyskinesia was “moderate” and 3–4 Hz of dyskinetic oral movements were dominant. “Extremely severe” and repetitious gross oral movements (around 1 Hz) were observed within a few minutes after injection and continued for up to 1 h. Thereafter, oral movements tended to decrease, and they disappeared completely 3 weeks after injection. This biphasic and long-lasting effect of ceruletide on tardive dyskinesia might contribute to further understanding of the physio-pathophysiological role of cholecystokinin-like peptides in the brain, and provide a basis for practical treatment of tardive dyskinesia.

Clonidine Therapy for Tardive Dyskinesia and Related Syndromes

Twenty-nine patients with tardive dyskinesia (n = 20) or related syndromes [spontaneous dyskinesia (n = 3), levodopa-induced dyskinesia (n = 3), tardive dystonia (n = 3)] were treated with clonidine. Clinical effects of this drug were observed for up to 4 years. Seventy-five percent of patients showed at least moderate improvement, and in 50% of patients, full resolution occurred. In most cases, patients received concomitant medications, including neuroleptics and benzodiazepines. Two patients received clonidine alone, and dyskinesia was only minimally improved; however, when bromocriptine was added, prompt improvement occurred on this combined regimen. On the basis of these findings, we suggest that not only receptor supersensitivity of dopaminergic neurons but also involvement of noradrenergic neurons is important in the pathophysiology of tardive dyskinesia and related syndromes.

Effect of ceruletide on tardive dyskinesia: a pilot study of quantitative computer analyses on electromyogram and microvibration

Seven patients with bucco-lingual dyskinesia were treated with a single dose of ceruletide 0.8 μg/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.

Prophylactic effects of neuroleptics in symptom-free schizophrenics: Roles of dopaminergic and noradrenergic blockers

A clinical trial was undertaken to determine the role of dopaminergic and noradrenergic blockers in the maintenance treatment of remitted schizophrenics. One hundred and six remitted schizophrenic outpatients were treated with one of nine treatments, viz., thioridazine 25 mg or 75 mg, pimozide 2 mg or 6 mg, and their respective combinations, for 1 year in a double-blind controlled study employing a randomized design. The data from a previous study were utilized as a retrospective placebo group. Pimozide prolonged the number of symptom-free days in a dose-dependent manner and did so more markedly than thioridazine. Combined administration of pimozide and thioridazine prolonged the number of symptom-free days to a greater extent than their single administration. However, an inverted U-shaped dose-response curve was obtained with the combined administration of these agents. These data suggest that both the dopaminergic and noradrenergic blocking action of neuroleptics are important in preventing relapse in remitted schizophrenics.

Prophylactic effect of neuroleptics in symptom-free schizophrenics

Prophylactic effects of psychotropic drugs on 55 schizophrenics in remission were evaluated for 3 years in a double-blind controlled study employing a cross-over design. Patients were randomly assigned to the following drugs orally administered twice a day: placebo; diazepam 15 mg; imipramine 50 mg; chlorpromazine 75 mg; and haloperidol 3 mg. The number of days of remission for each patient was recorded. Since only two patients received all five drug treatments, the data were analyzed using the number of days allocated to the “first assigned drugs” only and the cross-over aspect of the experimental design was disregarded. All patients treated with either the placebo, diazepam or imipramine relapsed within a year. On the other hand, four patients treated with chlorpromazine, or with haloperidol, were in remission for more than 1 year. Fifty percent of the patients relapsed within 16 days with placebo; 88 days with diazepam; 30 days with imipramine; 165 days with chlorpromazine; and 74 days with haloperidol. Within a year, only chlorpromazine significantly prolonged the remission state as compared to placebo and imipramine. At the end of the 3-year trial, both chlorpromazine and haloperidol significantly prolonged the remission state as compared to the other three drugs. These data suggest that neuroleptic treatment for a longer period is vitally important to prevent relapse even in schizophrenics in remission and that such a trial seems an efficient method for investigating the prophylactic effects of neuroleptics.

Naloxone Attenuates Drinking Behavior in a Schizophrenic Patient Displaying Self-induced Water Intoxication

This study was performed to examine the effect of naloxone on drinking behavior in a schizophrenic inpatient with psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome). His body weight was checked five times daily, and the maximum and minimum weight gains during a day were chosen as an index of polydipsia. Both daily (0.6 mg) and repeated (0.6 mg for 6 days) injections of naloxone suppressed his weight gain significantly for 2 weeks. Withdrawal of the drug for 4 weeks resulted in weight gain recovering to control level. Thereafter, a second trial was performed to examine the long-term effect of this treatment. A daily naloxone (0.6 mg) injection series was performed once every 2 weeks for six series (12 weeks). This drug regimen also suppressed his weight gain in a continuous fashion. The study showed that naloxone seems to be a potential treatment for PIP syndrome and that endogenous opioid systems play a part in the compulsive drinking behavior of the PIP syndrome.

Prophylactic effect of neuroleptics in symptom-free schizophrenics: A comparative dose-response study of haloperidol and propericiazine

Remitted schizophrenic outpatients were treated in order to prevent relapse with three doses of haloperidol or propericiazine for 1 year in a double-blind controlled study employing a randomized design. The drugs ability to prevent relapse was evaluated by counting the number of symptom-free days for each patient before any sign of relapse or over-dose appeared. Patients were randomly assinged to the following drugs orally administered once per day at night: placebo; haloperidol 1 mg, 3 mg, and 6 mg; propericiazine 10 mg, 30 mg, and 60 mg. Serum prolactin levels in each patient were estimated by radioimmunoassay. All patients treated with placebo relapsed within 1 year and the relapse rate with placebo was significantly higher than with any dose of the two neuroleptics. Haloperidol increased the number of symptom-free days in a dose-dependent manner. Propericiazine at 10 mg and 30 mg also increased the number of symptom-free days dose-dependently but at 60 mg, the number decreased. It appears that propericiazine shows an inverted U-shaped dose-response curve. Prolactin levels were elevated dose-dependently by both drugs but failed to show a significant correlation with the number of symptom-free days. The present results indicate that haloperidol is superior to propericiazine from the viewpoint of the wider “therapeutic window” in maintenance treatment and antidopaminergic properties of neuroleptics, wherein it is important to prevent relapse even in remitted schizophrenics.

Life-threatening dysphagia following prolonged neuroleptic therapy

We report the cases of two patients with complaints of dysphagia following long-term neuroleptic therapy. Esophageal contrast radiography revealed that one patient suffered disruption of the normal swallowing activity of the pharyngoesophagus due to tardive dyskinesia. Her dysphagia disappeared following changes in her neuroleptic medications and the administration of clonazepam. The other patient demonstrated severe rabbit syndrome involving the glossopharynx. This 3-Hz rhythmic movement disorder resolved following injection of an anticholinergic agent. Thereafter, the addition of oral trihexyphenidyl to her medication regimen improved her dysphagia. It should be emphasized that the differential diagnosis of neuroleptic-associated dysphagia subtypes is important because therapeutic strategies differ depending on the subtype of this life-threatening illness.

Combined treatment of tardive dyskinesia with clonidine and neuroleptics: a follow-up study of three cases for three years.

Three cases of tardive dyskinesia with psychotic symptoms (one presenile psychosis; two schizophrenia) were successfully treated with both clonidine and neuroleptics for 3 years. The dyskinesia abolished or reduced by clonidine returned several months after discontinvation of clonidine. During the follow-up study, it was observed that combining neuroleptics with clonidine was superior to thioridazine, levomepromazine, or sulpiride for controlling the dyskinesia. These findings suggest that noradrenergic involvement is important in tardive dyskinesia and that other subtypes of dyskinesia might exist.

Prevalence of and risk factors for respiratory dyskinesia

We explored the prevalence of respiratory dyskinesia (RD), diagnosed objectively using a spirograph, and the major risk factors for tardive dyskinesia (TD) and RD. A total of 258 inpatients treated with neuroleptics was interviewed, and TD was evaluated using the Abnormal Involuntary Movement Scale (AIMS). Movement of the chest and respiratory regularity were assessed on clinical examination. Spirographs of patients with suspected RD were recorded, and RD was diagnosed based on spirographic data and the concurrence of two investigators. The prevalence of TD in this study was 22.1% (57 of 258). Aging and organic brain damage (OBD) were confirmed as risk factors; female gender, mood disorders, and the duration of neuroleptic exposure were not. Ten of 28 patients suspected of having RD were diagnosed with RD on the basis of persistent respiratory irregularities without other physiologic causes. The overall prevalence of RD was 3.9% (10 of 258) and was 17.5% (10 of 57) among the TD patient population. Four of these patients complained of dyspnea, and three demonstrated grunting. RD was more highly associated with aging and OBD than with TD itself. The identification of risk factors for RD is not only helpful in planning prophylactic strategies, but also facilitates the understanding of the pathogenesis of this syndrome.