Relationships Between Drug Concentrations in Serum and CSF, Clinical Effects and Monoaminergic Variables in Schizophrenic Patients Treated with Sulpiride or Chlorpromazine

Alfredsson, Gunnel; Bjerkenstedt, Lars; Edman, Gunnar; Härnryd, C; Oxenstierna, Gabriel; Sedvall, Göran; Wiesel, Frits‐Axel

doi:10.1111/j.1600-0447.1984.tb06859.x

Cited by 54 publications

(27 citation statements)

References 21 publications

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“…All patients had measurable amounts of sulpiride or chlorpromazine in serum both in the morning and during the second PET investigation (Table 3). The drug concentrations were in accordance with previous findings (Alfredsson et al 1984). …”

Section: Regions Of Interestsupporting

confidence: 87%

Effects of sulpiride and chlorpromazine on regional cerebral glucose metabolism in schizophrenic patients as determined by positron emission tomography

et al. 1989

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Positron emission tomography (PET) was used to determine regional brain glucose metabolism in schizophrenic patients (n = 17) before and during neuroleptic treatment. The patients had not been treated with neuroleptics for at least 3 weeks before the first study. All suffered from acute psychotic symptoms and were hospitalized to obtain neuroleptic treatment. After determination of regional brain metabolism without neuroleptic treatment, 11 patients were treated with sulpiride (800 mg/day) and 6 patients were treated with chlorpromazine (400 mg/day) over 5-6 weeks before the second PET investigation. The control group consisted of seven healthy male volunteers, also investigated twice 5 weeks apart. The PET investigation was made with the subject in a resting state. The tracer was uniformly labelled 11C-glucose. The metabolism was determined bilaterally in 15 brain regions cortical, as well as central regions. Metabolic rates differed among the groups. The sulpiride group had lower metabolic rates than the controls and the schizophrenic patients later treated with chlorpromazine. The sulpiride group, in which absolute metabolic rates were determined, were clinically more autistic and chronic than the chlorpromazine group. It was proposed that these facts could explain the lower metabolic rates in the sulpiride group. A significant change in metabolism in relation to drug treatment was only found in one brain region. The selective D2-receptor antagonist sulpiride increased the metabolic rate in the right lentiform nucleus in comparison with the patients treated with chlorpromazine and the controls. Likewise, relative metabolic rates were increased only in the right lentiform nucleus. Negative correlations between intensity of clinical symptoms and metabolism indicated that emotional tone and drive were related to brain metabolism. No correlations were found between drug concentrations and metabolism or clinical symptoms.

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Section: Regions Of Interestsupporting

confidence: 87%

Effects of sulpiride and chlorpromazine on regional cerebral glucose metabolism in schizophrenic patients as determined by positron emission tomography

et al. 1989

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“…Different antipsychotic drugs and drug metabolites may, however, have different 44 blood-brain distribution ratios because of differences in protein binding in both plasma and CSF (Alfredsson et al 1982(Alfredsson et al , 1984aNyberg et al 1981;Wode-Helgodt & Alfredsson 1981). The dopamine receptor-blocking activity in plasma of psychiatric patients may, therefore, not be directly correlated to neuroleptic-induced dopamine receptor-blocking activity in the brain.…”

Section: Influence Of Blood-brain Distribution On Results Using Radiomentioning

confidence: 91%

“…In a more recent study involving 20 psychotic patients the same group found a significant correlation between reduction in CPRS morbidity scores and chlorpromazine serum concentrations 45 after 1 to 2 weeks, but not after 4 and 8 weeks' treatment with chlorpromazine 400 mg/day (Alfredsson et al 1984a(Alfredsson et al ,b, 1985. The serum chlorpromazine concentrations after 2 weeks' treatment [mean value 88 ± 18 nmol/L (28 ± 6 ILg/L)] were below 200 nmol/L (64 ILg/L) in all but 1 of the 20 patients studied.…”

Section: Concentrations Associated With Therapeutic Responsementioning

confidence: 91%

Plasma Level Monitoring of Antipsychotic Drugs Clinical Utility

Dahl

1986

Clinical Pharmacokinetics

145

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The steady-state plasma concentrations of antipsychotic drugs show large interpatient variations but remain relatively stable from day to day in each individual patient. Monitoring of antipsychotic drug concentrations in plasma might be of value provided the patients are treated with only 1 antipsychotic drug. Some studies have reported a relationship between therapeutic response and serum antipsychotic drug 'concentrations' as measured using the radioreceptor assay (RRA) method, which measures dopamine receptor-blocking activity in plasma. Most studies, however, have failed to demonstrate such a relationship, and the RRA does not seem to provide the generally useful tool for plasma concentration monitoring of antipsychotic drugs that was hoped for initially. A lack of correlation between dopamine receptor-blocking activity in plasma and therapeutic response may be due to differences in the blood-brain distribution of both antipsychotic drugs and their active metabolites. Chemical assay methods (e.g. GLC and HPLC) have been used in studies which examined the relationships between therapeutic response and antipsychotic drug concentrations in red blood cells and in plasma. It seems that for these drugs, measuring red blood cell concentrations does not offer any significant advantage over measuring plasma concentrations. Reasonably controlled studies of plasma concentration-response relationships using randomly allocated, fixed dosages of chlorpromazine, fluphenazine, haloperidol, perphenazine, sulpiride, thioridazine and thiothixene have been published but often involve relatively few patients. A correlation between therapeutic response and plasma concentrations of thioridazine and its metabolites has not been demonstrated, and plasma level monitoring of thioridazine and its metabolites therefore appears to have no clinical value. Clinical behavioural deterioration concomitant with high plasma concentrations of chlorpromazine and haloperidol have been reported. A dosage reduction might be considered after 2 to 4 weeks' treatment in non-responders who have plasma chlorpromazine concentrations above 100 to 150 micrograms/L or plasma haloperidol concentrations above 20 to 30 micrograms/L. Non-responders and good responders to chlorpromazine treatment, however, have plasma drug concentrations in the same range, and a therapeutic range of plasma chlorpromazine levels has not been defined. Therapeutic plasma haloperidol concentrations (i.e. 'window') in the range of 5 to 20 micrograms/L have been reported by some investigators, but others have found no such relationship.(ABSTRACT TRUNCATED AT 400 WORDS)

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“…They are understandably 233 counterproductive from a therapeutic point of view. This might explain why some investigators have found an 'inverted U' or 'bell-shaped' concentration-response curve for antipsychotic drugs (Alfredsson et al 1984;Johnstone et al 1983). In addition, it does not seem that using free (i.e.…”

Section: Concentration-effect Relationshipsmentioning

confidence: 95%

Pharmacokinetic Optimisation of the Treatment of Psychosis

Balant-Gorgia¹,

Balant

Andréoli³

1993

Clinical Pharmacokinetics

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Psychosis is a generic term covering (for the purposes of the present article)) schizophrenia, brief reactive psychoses and manic episodes. Traditionally, research has focused on the effect of antipsychotic agents on positive or productive symptoms such as hallucinations or delusions. More recently, attention has been focused on negative symptoms such as emotional withdrawal or impairment of social participation. Typical antipsychotic medications such as phenothiazines have little effect on these clinical manifestations. This has raised interest in atypical antipsychotics such as clozapine. Acute psychotic episodes are less difficult to treat than long term schizophrenic manifestations. Current research indicates that antipsychotics are effective only if a threshold concentration is reached, but that above a certain level, dose escalation is of no benefit to the patient. This implies the existence of an optimal therapeutic concentration range. Due to interindividual variability caused by age, genetic and interethnic factors or drug-drug interactions, antipsychotic plasma concentrations show a wide range of values for the same dosage regimen. This is why clinical pharmacokinetic principles and therapeutic drug monitoring are essential tools for dosage individualization. Clinical pharmacokinetics in therapeutics implies that the pharmacokinetic parameters of the medication under scrutiny are known. This is, however, not always the case with antipsychotics since, due to the difficulties encountered in conducting phase I studies in healthy volunteers with these substances, published data are not always complete.

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Relationships Between Drug Concentrations in Serum and CSF, Clinical Effects and Monoaminergic Variables in Schizophrenic Patients Treated with Sulpiride or Chlorpromazine

Cited by 54 publications

References 21 publications

Effects of sulpiride and chlorpromazine on regional cerebral glucose metabolism in schizophrenic patients as determined by positron emission tomography

Effects of sulpiride and chlorpromazine on regional cerebral glucose metabolism in schizophrenic patients as determined by positron emission tomography

Plasma Level Monitoring of Antipsychotic Drugs Clinical Utility

Pharmacokinetic Optimisation of the Treatment of Psychosis

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