We previously described a Swedish set of male schizophrenic monozygotic triplets. In this study the patients as well as their parents were further characterized. By high-resolution chromosomal analysis an extra band at chromosome 15p was found in all the triplets and the father. Microdissection, degenerate oligonucleotide-primed PCR (DOP-PCR) amplification and reverse painting indicates that the extra band probably contains only repetitive DNA sequences with no known effect on the phenotype. Magnetic resonance imaging (MRI) showed similar borderline ventricular enlargement and widened subarachnoid spaces over frontoparietal and basal regions as well as around the pituitary gland (empty sella) in all the triplets. The father also had widened subarachnoid spaces over the frontal and basal regions. The mother had an empty sella indicating widened subarachnoid spaces. All the boys also had a right-sided conductive hearing defect, probably due to malformation and fixation of the ossicular chain. The parents did not present any otological abnormalities. Neuropsychological assessment demonstrated similar marked reductions of attentional, mnestic, and executive functions in all the triplets, but the mother showed a normal pattern. Possible joint etiological mechanisms for the psychological and somatic abnormalities recorded in the triplets are discussed.

SCH 39166 is the first selective D1 dopamine receptor antagonist developed for the treatment of schizophrenic patients. To examine potential antipsychotic effect, tolerability and safety, SCH 39166 was given orally to 17 acutely ill drug free schizophrenic patients (DSMIIIR) in an open 4-week study. Doses were escalated from 10 to 100 mg b.i.d. according to a fixed schedule over 17 days and remained at 100 mg b.i.d. for another 11 days. The drug was withdrawn prematurely in ten patients because of deterioration or refusal to take SCH 39166. In the nine patients participating for more than 2 weeks, none had an apparent reduction of BPRS or CGI scores. Side effects were agitation, akathisia and emesis in single patients. After withdrawal of SCH 39166 of the patients improved when treated with classical neuroleptics or clozapine. The result of the study does not support the prediction that selective D1 dopamine receptor antagonism will produce antipsychotic effects in schizophrenia.

A set of schizophrenic male monozygotic triplets is described. At age 20 years, within 8 months the three men independently developed acute fulminant schizophrenic disorders (DSM-III-R) with auditory hallucinations, bizarre delusions, and thought disturbances. There were also great similarities between the triplets with regard to the chronic intermittent course of the disorder, impairment of social adjustment, and loss of working ability. The psychoses responded rapidly to conventional neuroleptic treatment. neuropsychological assessment demonstrated similar marked reductions of attentional, mnestic, and executive functions. Magnetic resonance imaging (MRI) showed similar borderline ventricular enlargement and widened subarachnoid spaces over frontoparietal and basal regions as well as around the pituitary gland (empty sella). All the boys also had a right-sided hearing defect with a marked reduction of the ossicular bones on the right side. Possible clues as to etiological mechanisms were the lack of reported family history for the disorder and a possible influenza infection in the mother during the first trimester. It is suggested that a DNA aberration being present or occurring at conception initiated a precise timeprogrammed series of events that produced the very similar schizophrenic phenotypes. Such an aberration might have been induced by an external agent, occurred spontaneously, or been inherited by a recessive mechanism. It seems possible that the psychoses, the reductions of neuropsychological functions, the morphological MRI changes, and the right-sided ossicular reductions may all be related to such a DNA alteration.

ABSTRACT Twenty schizophrenic women participated in a double‐blind comparison of melperone (300 mg daily) and placebo lasting 4 weeks. All the patients received milieu treatment. Two patients in the melperone and four in the placebo group were removed from the study due to unsatisfactory therapeutic response. In the melperone group, there were significant reductions in psychotic morbidity. In the placebo group, there were occasional significant redutions of psychotic morbidity during but not at the end of treatment. The melperone‐treated patients exhibited significantly lower morbidity scores than the placebo group after treatment for two and four weeks. The melperone group demonstrated significantly more adverse reactions than placebo‐treated patients at the end of the study. The results support the view that melperone exerts an antipsychotic effect. The study is consistent with the opinion that milieu therapy should be combined with neuroleptics to achieve an optimal result in the treatment of an acute phase of schizophrenia.

Schizophrenic patients were treated with fixed doses of sulpiride (800 mg) or chlorpromazine (400 mg) during eight weeks using a double-blind design. In order to examine relationships between pharmacokinetic, clinical and biochemical parameters in relation to treatment the following variables were recorded before and 1, 2, 4 and 8 weeks after treatment. Concentrations of sulpiride, CPZ, 7-OH-CPZ, nor1-CPZ were determined in serum and CSF using liquid chromatography and mass fragmentography. Clinical variables were psychotic morbidity and side effects as evaluated by CPRS, NOSIE and side effect ratings. Monoaminergic variables were concentrations of the major cerebral monoamine metabolites, HVA, 5-HIAA and MOPEG in the cerebrospinal fluid as measured by mass fragmentography. Prolactin levels in serum and CSF were measured by radioimmunoassay. During steady state, concentrations of sulpiride in serum varied fourfold between patients and CPZ twentyfold. Drug concentrations in serum and CSF were highly correlated in CPZ-but not in sulpiride-treated patients. Although sulpiride passed into the CSF, transport between serum and CSF was restricted. In the sulpiride group, improvement of psychotic morbidity and HVA elevation in CSF tended to be negatively related to the drug concentrations in serum. Sulpiride-treated patients with extrapyramidal side effects had significantly higher drug concentrations in serum. In CPZ-treated patients, improvement of psychotic morbidity, HVA elevation and prolactin elevation all tended to be positively correlated to drug concentrations in serum and CSF. CPZ-treated patients with extrapyramidal side effects also had significantly higher CPZ concentrations in serum. In both treatment groups, the MOPEG reduction in CSF tended to be correlated to improvement of psychotic morbidity. The study supplied clinical evidence for the view that antipsychotic drugs belonging to the phenothiazine and benzamide series induce antipsychotic effects in schizophrenic patients in a graded fashion which is proportional to the degree of interaction with the central dopaminergic mechanisms. The results also support the view that sulpiride has a more selective effect on central dopaminergic mechanisms than chlorpromazine. In the schizophrenic patients studied and with the doses used, sulpiride concentrations tended to be maximal with regard to clinical and biochemical effects. For CPZ on the other hand, drug concentrations in some patients seemed to be too low to induce optimal effects.

Schizophrenic patients were treated with fixed doses of sulpiride (800 mg/day) or chloropromazine (CPZ) (400 mg/day) over a period of 8 weeks using a double-blind design. There were 25 patients in each group and all the patients were in an acute phase of their disease. They all fulfilled the Research Diagnostic Criteria (RDC) for schizophrenia. Depressive symptoms as rated according to the Comprehensive Psychopathological Rating Scale (CPRS) were present in the patients before treatment was started. The depressive and psychotic symptoms in both groups decreased in parallel during the whole period of treatment. Patients in the sulpiride group recovered more quickly from depressive symptoms than patients in the CPZ group. It was also found that patients with low concentrations of sulpiride or CPZ in serum recovered more completely from depressive symptoms and had fewer extrapyramidal side effects than patients with high drug concentrations.

To evaluate the clinical potential of sulpiride for the treatment of schizophrenic patients, a double-blind study was performed comparing fixed doses of sulpiride (800 mg daily) and chlorpromazine (400 mg daily). Twenty-five schizophrenic (RDC) patients participated in each treatment group. Antipsychotic effects were evaluated by CPRS and NOSIE ratings before and after 1, 2, 4 and 8 weeks of treatment. Interrater reliabilities for CPRS items and subscales were satisfactory. Treatment with sulpiride or chlorpromazine resulted in a significant reduction of psychotic morbidity as estimated by CPRS and global ratings. CPRS scores reflecting autism were significantly reduced in all ratings of sulpiride-treated patients, but only after four weeks in the chlorpromazine group. Total NOSIE scores indicated improvement in both treatment groups. A significant difference in favour of sulpiride was obtained for the NOSIE subscale "retardation". Extrapyramidal side effects occurred at a similar frequency in both treatment groups. Autonomic side effects occurred to a greater extent in chlorpromazine-treated patients. Lactation was reported only in four sulpiride-treated patients. Liver transaminase enzymes in serum were markedly elevated only in chlorpromazine-treated patients. The results indicate that sulpiride has a marked antipsychotic effect which is at least not inferior to that of chlorpromazine. A better effect on autistic components of behaviour was demonstrated for sulpiride. The results indicate a higher risk of lactation but a lower risk of anticholinergic side effects and liver toxicity for treatment with sulpiride than with chlorpromazine.

Concentrations of the major monoamine metabolites homovanillic acid (HVA) 4-hydroxy-3-methoxyphenylethylene glycol (MOPEG), and 5-hydroxyindoleacetic acid (5-HIAA) were determined in lumbar CSF of psychotic women with a schizophrenic symptomatology before and 4 weeks after treatment with sulpiride (Dogmatil 200 mg×4). The metabolites were determined by a mass fragmentographic method. Prolactin concentrations in CSF and plasma were determined by radioimmunoassay. The clinical effects were evaluated by ratings according to the comprehensive psychopathology rating scale (CPRS) and a scale for side effects. Levels of HVA and prolactin in CSF and plasma were significantly elevated during treatment. No effects on concentrations of MOPEG or 5-HIAA were observed. The biochemical data indicate that clinical doses of sulpiride blocked dopamine receptors in the nigrostriatal pathway as well as in the tuberoinfundibular system. Treatment with sulpiride was associated with marked reductions in psychotic morbidity.

The effect of ECT on concentrations of monoamine metabolites in lumbar CSF of psychotic women with a schizophrenic symptomatology was examined. After a series of ECT there was a significant reduction of the concentration of the major noradrenaline metabolite, MOPEG. Levels of HVA, 5-HIAA, prolactin, or total protein in CSF were not significantly influenced by treatment. The results indicate a specific alteration of central noradrenaline metabolism in relation to ECT.

Clinical and biochemical effects of melperone (100 mg × 3) and thiothixene (10 mg × 3) were studied in women with psychoses of schizophrenic or paranoid type. Psychotic morbidity and side effects were determined by rating scales. Concentrations of the major monoamine metabolites homovanillic acid (HVA), 4-hydroxy-3-methoxyphenyl-ethylene glycol (MOPEG), and 5-Hydroxy-3-indoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) were measured by mass fragmentography. Concentrations of prolactin in CSF and plasma were determined by radioimmunoassay (RIA). Measurements were performed before and after 2 and 4 weeks of drug treatment.

Eighty-one women with psychosis of schizophrenic and paranoid type were assigned to a double-blind study comparing the clinical effects of melperone (l00 mg × 3) and thiothixene (10 mg × 3). The antipsychotic effect was evaluated by clinical rating according to the CPRS and the NOSIE-30 scales before and after 2 and 4 weeks of drug treatment. A satisfactory interrater reliability was obtained for the CPRS. Significant correlation was also found between the CPRS and NOSIE ratings.

Levels of prolactin (PRL) were determined by radioimmunoassay in cerebrospinal fluid (CSF) and plasma from psychotic women before and during treatment with melperone 100 mg×3 (n=29) or thiothixene 10 mg×3 (n=34). Small amounts of PRL were found in the CSF of most patients before treatment. The level of PRL in CSF was about 20% of that in the plasma. Both drugs elevated PRL levels in CSF and plasma significantly. Thiothixene was more potent and also more long acting than melperone in this regard. For neither drug was there any marked tolerance to the effects within a 4 week period. The highest PRL level in CSF, 26 ng/ml, was found in a thiothixene treated patient.

Psychotic women with schizophrenic symptoms were treated with melperone 100 mg×3 (n=29) or thiothixene 10 mg×3 (n=34) using a double-blind procedure. Before and during treatment, levels of HVA, MOPEG, and 5-HIAA, the major metabolites of DA, NE, and 5-HT, were determined in lumbar cerebrospinal fluid by a mass fragmentographic technique. Both treatments resulted in an elevation of the HVA levels after 2 weeks, thiothixene having a more marked effect. The effect of thiothixene but not of melperone persisted after 4 weeks. Thiothixene did not influence the MOPEG level, but melperone reduced it after 4 weeks of treatment. The 5-HIAA levels were not significantly altered by the drugs. The HVA/MOPEG and the HVA/5-HIAA ratios were highly significantly elevated by both drugs after 2 as well as 4 weeks. Thiothixene induced a significantly greater change of these ratios than melperone. The results supply evidence that thiothixene accelerates central dopamine metabolism in man, presumably by blocking DA receptors. Melperone appears to act similarly, but has an effect which is weaker and/or of shorter duration. During long-term treatment with melperone the receptors develop tolerance to it. The acceleration in DA metabolism declines and the effect of melperone switches instead to central NA metabolism. The results indicate that both drugs cause long-term changes in the activity ratios of central monoamine systems. It is suggested that such changes in several systems rather than single biochemical events may be related to the antipsychotic effects of neuroleptic drugs. This study also demonstrated the versatility of using monoamine metabolite analysis of the CSF as a tool for the quantification of biochemical effects of neuroleptic drugs on the human CNS.

The present paper summarizes work carried out at the Karolinska Institute, Stockholm, Sweden, over the last few years. The studies deal with the possibility of finding chemical parameters useful for the selection of drugs and their dosage to treat psychotic patients.