Clozapine serum levels and side effects during steady state treatment of schizophrenic patients: a cross-sectional study

Abstract

Serum clozapine (S-Cloza) and serum desmethyl-clozapine concentrations (S-Descloza) were measured in 30 chronic schizophrenic in- and out-patients on a variable dose regimen. All patients were in steady state with respect to clozapine therapy and in a stable condition with respect to psychotic illness. The 24-h clozapine dose (median with interquartile range in parenthesis) was 350 (228-425) mg/24 h (range 100-700). There was a weak positive correlation between doses and the BPRS total score (r = 0.44, P < 0.05). The median S-Cloza was 1076 (706-1882) nmol/l (range 196-5581 corresponding to 64-1824 ng/ml). The S-Cloza was linearly correlated to dose but with a high interindividual variation at equal doses, e.g. a factor of 8 at 400 mg/24 h, but a low intraindividual variability of 20%. The S-Descloza averaged 77% of the S-Cloza and was highly correlated to S-Cloza (r = 0.90; P < 0.001). The S-Descloza/dose ratio increased with age and duration of treatment. The side effects registered were EEG abnormalities (83%), tachycardia (23%), increased liver enzyme activity (60%), orthostatic hypotension (17%), and moderate leucocytosis (17%). Only EEG changes were correlated to S-Cloza (r = 0.43; P < 0.05). The score values of the UKU Side Effect Scale were weakly (r = 0.36) correlated to S-Cloza. No side effects were correlated to S-Descloza, doses, or treatment duration. The frequency of side effects was higher than in studies using lower mean doses indicating a correlation between doses or S-Cloza and the frequency of side effects. It is concluded that clozapine fulfils the criteria for therapeutic drug monitoring. TDM may contribute to finding the lowest effective dose with the fewest possible side effects.

N-Desmethylclozapine, a Major Clozapine Metabolite, Acts as a Selective and Efficacious δ-Opioid Agonist at Recombinant and Native Receptors

“…Nonetheless, these values are within the range of NDMC plasma concentrations (175-435 ng/ml; 0.6-1.4 mM) measured in schizophrenics following chronic treatment with clozapine (Centorrino et al, 1994;Olesen et al, 1995;Aravagiri and Marder, 2001;Frazier et al, 2003). The concentrations reached by NDMC in the human brain under these conditions are unknown.…”

“…Whereas CNOX can be rapidly re-converted to clozapine, NDMC reaches considerable plasma concentrations ranging from 49 to 140% of those of the parent compound in schizophrenic patients (Centorrino et al, 1994;Olesen et al, 1995;Aravagiri and Marder, 2001;Frazier et al, 2003) and from 50 to 220% in the rat (Baldessarini et al, 1993;Weigmann et al, 1999). In the rat brain, concentrations of NDMC higher than those in serum have been detected following clozapine administration, indicating that the metabolite can cross the blood-brain barrier (Weigmann et al, 1999).…”

Therapeutic drug monitoring of atypical antipsychotic drugs

“…There is also a relationship between serum clozapine concentrations and CNS adverse effects. For example, Olesen et al (31) found a significant correlation between clozapine concentrations and EEG changes. Concentrations above 1000 ng mL -1 significantly increased the risk of confusion, delirium and generalized seizures (31,32).…”

Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors

“…In addition, the average ratio between norclozapine and clozapine is 0.59, [49][50][51][52][53][54][55] resulting in a norclozapine concentration of 106 nM in the spinal fluid. However, because norclozapine has a dissociation constant of 100 nM at D2, compared to a value of 44 nM for clozapine (Table 1), the spinal fluid concentration of 106 nM norclozapine is equivalent to a 'clozapine-like D2-blocking concentration' of 106 nM × 44 nM/100 nM or 47 nM.…”