Brain and plasma pharmacokinetics of aripiprazole in patients with schizophrenia: an [18F]fallypride PET study.
ABSTRACT Aripiprazole at clinically effective doses occupies some 90% of striatal dopamine 2 and 3 (D(2)/D(3)) receptors. In order to further characterize its extrastriatal and time-dependent binding characteristics, the authors conducted positron emission tomography (PET) studies with the D(2)/D(3) antagonist [(18)F]fallypride at varying time points after the last aripiprazole administration in patients with schizophrenia.
Sixteen inpatients with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder receiving treatment with aripiprazole underwent an [(18)F]fallypride PET scan. Receptor occupancy was calculated as the percentage reduction in binding potential relative to unblocked values measured in eight age-matched, medication-free patients with schizophrenia. In addition, aripiprazole serum concentrations were determined as part of a routine therapeutic drug monitoring program in a large group of patients (N=128) treated with aripiprazole.
Mean dopamine D(2)/D(3) receptor occupancy was high in all brain regions investigated, with no binding difference across brain regions. Nonlinear regression analysis revealed maximum attainable receptor occupancy (E(max)) values close to saturation. The values for serum concentration predicted to provide 50% of E(max) (EC(50)) were in the range of 5-10 ng/ml in all brain regions. The D(2)/D(3) receptors were completely saturated when serum aripiprazole concentration exceeded 100-150 ng/ml. The mean concentration in the large clinical patient sample was 228 ng/ml (SD=142).
Because of its high affinity for D(2)/D(3) receptors and its long elimination half-life, aripiprazole at clinical doses occupies a high fraction of its target receptor everywhere in the brain. Its dissociation from those receptors is very slow, such that the authors calculate from the results that in patients with serum aripiprazole concentrations in the range typical for clinical practice, D(2)/D(3) receptors must remain nearly saturated for as long as 1 week after the last dose.
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ABSTRACT: In the field of schizophrenia research, as in other areas of psychiatry, there is a sense of frustration that greater advances have not been made over the years, calling into question existing research strategies. Arguably, many purported gains claimed by research have been "lost in translation," resulting in limited impact on diagnosis and treatment in the clinical setting. There are exceptions; for example, we would argue that different lines of preclinical and clinical research have substantially altered how we look at antipsychotic dosing. While this story remains a work in progress, advances "found in translation" have played an important role. Detailing these changes, the present paper speaks to a body of evidence that has already shifted clinical practice and raises questions that may further alter the manner in which antipsychotics have been administered over the last 6 decades.Journal of psychiatry & neuroscience: JPN 01/2014; 39(1):130191. · 6.24 Impact Factor
Article: Aripiprazole[Show abstract] [Hide abstract]
ABSTRACT: Aripiprazole is an atypical antipsychotic that has been shown to be more effective than placebo and at least as effective as haloperidol and risperidone in the treatment of schizophrenia and schizoaffective disorder. Despite having a well defined licensed dose range, the optimum dose for aripiprazole is yet to be established. Aripiprazole exhibits high affinity for dopamine D2 receptors, with near maximal receptor occupancy at a dose of 30 mg. Even doses as low as 2 mg, thought not to be clinically effective, have produced striatal D2 receptor occupancies exceeding 70%, higher than the accepted threshold for antipsychotic effect. In this review we examined the efficacy data from short-term studies of aripiprazole in relapsed schizophrenia or schizoaffective disorder, in order to establish a dose-response relationship for aripiprazole. Results of five fixed-dose studies suggest that the threshold for clinical effect is between 5 and 10 mg/day. In addition, the highest response rate is seen at 10 mg/day. Doses above 20 mg/day do not appear to provide any additional benefit and may be associated with a smaller change in symptom scores. In summary, the data available so far indicate that the optimum dose for aripiprazole is 10 mg/day and that doses above 20 mg/day provide no additional benefit.CNS Drugs 23(9). · 4.38 Impact Factor
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ABSTRACT: Blocking of the serotonin transporter (SERT) represents the initial mechanism of action of selective serotonin reuptake inhibitors (SSRIs) which can be visualized due to the technical proceedings of SERT occupancy studies. When compared to the striatum, higher SERT occupancy in the midbrain and lower values in the thalamus were reported. This indicates that occupancy might be differently distributed throughout the brain, which is supported by preclinical findings indicating a regionally varying SERT activity and antidepressant drug concentration. The present study therefore aimed to investigate regional SERT occupancies with positron emission tomography and the radioligand [(11)C]DASB in 19 depressed patients after acute and prolonged intake of oral doses of either 10mg/day escitalopram or 20mg/day citalopram. Compared to the mean occupancy across cortical and subcortical regions, we detected increased SERT occupancies in regions commonly associated with antidepressant response, such as the subgenual cingulate, amygdala and raphe nuclei. When acute and prolonged drug intake was compared, SERT occupancies increased in subcortical areas that are known to be rich in SERT. Moreover, SERT occupancy in subcortical brain areas after prolonged intake of antidepressants was predicted by plasma drug levels. Similarly, baseline SERT binding potential seems to impact SERT occupancy, as regions rich in SERT showed greater binding reduction as well as higher residual binding. These findings suggest a region-specific distribution of SERT blockage by SSRIs and stress the postulated link between treatment response and SERT occupancy to certain brain regions such as the subgenual cingulate cortex.NeuroImage 10/2013; · 6.25 Impact Factor