A dose-finding study of duloxetine based on serotonin transporter occupancy
ABSTRACT Positron emission tomography (PET) has been utilized for determining the dosage of antipsychotic drugs. To evaluate the dosage of antidepressants such as selective serotonin reuptake inhibitors, serotonin transporter occupancy (5-HTT) is also a useful index.
We investigated the degree of 5-HTT occupancy with different doses of the antidepressant duloxetine and the time-course of 5-HTT occupancy using PET.
PET scans with [11C]DASB were performed before and after a single administration of duloxetine (5-60 mg), and three consecutive scans were performed after a single dose or repeated doses of 60 mg of duloxetine.
5-HTT occupancies by duloxetine were increased by 35.3 to 86.5% with dose and plasma concentration increments. The ED50 value of 5-HTT occupancy was 7.9 mg for dose and 3.7 ng/ml for plasma concentration. In the time-course of 5-HTT occupancy, mean occupancies were 81.8% at 6 h, 71.9% at 25 h, and 44.9% at 53 h after a single administration, and 84.3% at 6 h, 71.9% at 49 h, and 47.1% at 78 h after repeated administrations.
Based on 5-HTT occupancy, 40 mg and more of duloxetine was needed to attain 80% occupancy, and 60 mg of duloxetine could maintain a high level of 5-HTT occupancy with a once-a-day administration schedule.
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- "fluoxetine or paroxetine) or serotonin-noradrenaline reuptake inhibitors (e.g. duloxetine ; Meyer et al. 2004 ; Takano et al. 2006 ; Talbot & Laruelle, 2002 "
ABSTRACT: The therapeutic effect of current antidepressant drugs appears after several weeks of treatment and a significant number of patients do not respond to treatment. Here, we report the effects of the multi-modal antidepressant vortioxetine (Lu AA21004), a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor, on rat 5-HT neurotransmission. Using in vivo electrophysiological recordings in the dorsal raphe nucleus of anaesthetized rats, we assessed the acute and subchronic effects of vortioxetine and/or the selective 5-HT3 receptor agonist, SR57227 or the selective 5-HT1A receptor agonist flesinoxan, on 5-HT neuronal firing activity. Using ex-vivo autoradiography, we correlated SERT occupancy and presumed 5-HT firing activity. The selective serotonin reuptake inhibitor, fluoxetine, was used as comparator. Importantly, the recovery of 5-HT neuronal firing was achieved after 1 d with vortioxetine and 14 d with fluoxetine. SR57227 delayed this recovery. In contrast, vortioxetine failed to alter the reducing action of 3 d treatment of flesinoxan. Acute dosing of vortioxetine inhibited neuronal firing activity more potently than fluoxetine. SR57227 prevented the suppressant effect of vortioxetine, but not of fluoxetine. In contrast, flesinoxan failed to modify the suppressant effect of vortioxetine acutely administered. Differently to fluoxetine, vortioxetine suppressed neuronal firing without saturating occupancy at the SERT. Vortioxetine produced a markedly faster recovery of 5-HT neuronal firing than fluoxetine. This is at least partly due to 5-HT3 receptor antagonism of vortioxetine in association with its reduced SERT occupancy.The International Journal of Neuropsychopharmacology 10/2012; 16(05):1-13. DOI:10.1017/S1461145712001058 · 5.26 Impact Factor
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- "The dose of duloxetine was 60 mg per day, which is the maximum dose recommended by the Food and Drug Administration for duloxetine in the treatment of major depression (Cymbalta United States product information sheet), was established at T0 and maintained until the end of the trial at week 16. It has been evidenced that duloxetine at a dose of 60 mg per day should be the dose necessary for sufficient binding-site occupancy (Bech et al., 2006; Takano et al., 2006), During the study, no additional medications were allowed. "
ABSTRACT: Antidepressant drugs have often been used as an augmentation strategy for those patients who have demonstrated a suboptimal response to clozapine. The present 16-week double-blind, randomized, placebo-controlled trial study aimed to explore the efficacy and tolerability of duloxetine add-on pharmacotherapy on clinical symptomatology and executive cognitive functioning in a sample of patients with treatment-resistant schizophrenia receiving clozapine. After clinical and neurocognitive assessments, the patients were randomly allocated to receive, in a double-blind design, at a dose of 60 mg per day of duloxetine or a placebo. A final sample of 33 patients completed the study. The results obtained indicate that duloxetine added to stable clozapine treatment showed a beneficial effect on the negative and general psychopathological symptomatology in a sample of treatment-resistant schizophrenic patients. With regard to executive cognitive functions, duloxetine augmentation of clozapine had no significant effects. The findings provide evidence that duloxetine augmentation of clozapine treatment is safe and well tolerated and may be of benefit for patients who are partially responsive to clozapine monotherapy.International clinical psychopharmacology 09/2011; 26(6):303-10. DOI:10.1097/YIC.0b013e32834bbc0d · 3.10 Impact Factor
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- "Prediction of RD occupancy from SD data S Abanades et al relevant anatomic regions, extraction of time-activity curves and kinetic modelling with the simplified reference tissue model to derive regional parameter estimates of receptor availability (BP ND ). The regional BP ND values for the midbrain, striatum, and thalamus were consistent with previous literature estimates (Takano et al, 2006). In addition, occupancy estimates for these three regions were similar within each postdose scan, i.e., a range of s.d. between regions within subjects of 1% to 14% with an average of 5%. "
ABSTRACT: Positron emission tomography (PET) is used in drug development to assist dose selection and to establish the relationship between blood and tissue pharmacokinetics (PKs). We present a new biomathematical approach that allows prediction of repeat-dose (RD) brain target occupancy (TO) using occupancy data obtained after administration of a single dose (SD). A PET study incorporating a sequential adaptive design was conducted in 10 healthy male adults who underwent 4 PET scans with [(11)C]DASB ([(11)C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine): 1 at baseline, 2 after 20 mg SD of the 5-hydroxytryptamine transporter (5-HTT) inhibitor duloxetine, and 1 after 4 days daily administration of 20 mg duloxetine. An adaptive design was used to select optimal times after SD for measurement of occupancy. Both direct and indirect PK/TO models were fitted to the SD data to characterise the model parameters and then applied to a predicted RD duloxetine plasma time course to predict the 5-HTT occupancy after RD. Repeat-dose prediction from the indirect model (OC(50)=2.62±0.93 ng/mL) was significantly better (P<0.05) than that from the direct model (OC(50)=2.29±1.11 ng/mL). This approach increases the value of SD occupancy studies that are performed as part of first time in human drug development programmes by providing an estimate of the dose required to achieve the desired TO at RD.Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 10/2010; 31(3):944-52. DOI:10.1038/jcbfm.2010.175 · 5.34 Impact Factor