Christer Härnryd

Lack of apparent antipsychotic effect of the D1-dopamine recepotr antagonist SCH39166 in acutely ill schizophrenic patients

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 The drug was withdrawn prematurely in ten patients because of deterioration or refusal to take SCH 39166.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

Effects of sulpiride and chlorpromazine on autistic and positive psychotic symptoms in schizophrenic patients —relationship to drug concentrations

Schizophrenic patients were treated with fixed doses of sulpiride (800 mg/day) or chlopromazine (CPZ) (400 mg/day) during a period of 8 weeks using a double-blind design. There were 25 patients in each group and all of them fulfilled the Research Diagnostic Criteria (RDC) for schizophrenia. Autistic and psychotic symptoms were rated with subscales developed from the Comprehensive Psychopathological Rating Scale (CPRS). Autistic symptoms were also rated with a subscale of the Nurses Observation Scale for Inpatient Evaluation (NOSIE). Sulpiride was superior to CPZ in reducing the autistic symptoms. Patients with low concentrations of sulpiride in serum had a better recovery rate from autistic symptoms than those with high concentrations. Both drugs reduced positive psychotic symptoms to the same degree.

Effects of melperone and thiothixene on prolactin levels in cerebrospinal fluid and plasma of psychotic women

SummaryLevels 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.Positive correlations were found between the contents of PRL in CSF and plasma before treatment. During thiothixene treatment there were also significant positive correlations between PRL levels in CSF and plasma. During melperone treatment this correlation was probably significant only after treatment for 4 weeks. Neither drug affected the levels of total protein in CSF. The results indicate that with the doses used thiothixene causes a more marked and long lasting blockade of central dopamine receptors controlling prolactin release. The study also demonstrated the versatility of using prolactin analyses of CSF and plasma as tools for quantitation of biochemical effects of neuroleptic drugs on the human central nervous system.

Monoamine metabolite levels in cerebrospinal fluid of psychotic women treated with melperone or thiothixene

SummaryPsychotic 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.

Effects of sulpiride and chlorpromazine on depressive symptoms in schizophrenic patients--relationship to drug concentrations.

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.

Reduction of MOPEG levels in cerebrospinal fluid of psychotic women after electroconvulsive treatment

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.

Relationships between clinical and biochemical effects of melperone and thiothixene in psychotic women

SummaryClinical 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.The drugs did not differ in antipsychotic effect, but thiothixene treatment caused greater elevation of HVA and prolactin than melperone. The measures of dopaminergic activity did not correlate significantly with therapeutic outcome in either of the treatment groups. Treatment with melperone, but not thiothixene, reduced MOPEG levels, but only during thiothixene treatment was MOPEG reduction related to clinical improvement. In both treatment groups clinical improvement correlated significantly with an increase in the 5-HIAA/MOPEG ratio. Extrapyramidal side effects correlated negatively with HVA and HVA/MOPEG in the thiothixene, but not in the melperone group.It is concluded that there is no simple relationship between alteration of dopaminergic transmission and therapeutic outcome in drug-treated psychotic patients. In addition to dopamine (DA) receptor blockade, alteration of norepinephrine (NE) mechanisms may play a role in the antipsychotic effect. It is suggested that the balance of activity between central serotonin (5-HT) and NE systems should be considered in the mechanism of action of antipsychotic drugs and the pathophysiology of psychosis.

Central Biochemical Correlates to Antipsychotic Drug Action in Man

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.

Further studies on a male monozygotic triplet with schizophrenia: cytogenetical and neurobiological assessments in the patients and their parents

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.

A set of male monozygotic triplets with schizophrenic psychoses: nature or nurture?

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.