P-glycoprotein differentially affects escitalopram, levomilnacipran, vilazodone and vortioxetine transport at the mouse blood-brain barrier in vivo.

P-glycoprotein (P-gp)-mediated brain efflux of xenobiotics is a well-known process, which may result in suboptimal target engagement and consequently reduced efficacy of drugs exerting their therapeutic effects in the central nervous system. In the present study the role of P-gp in transport across the blood-brain barrier (BBB) was investigated with a series of newer antidepressants (levomilnacipran, vilazodone and vortioxetine) and a control substrate (escitalopram) using P-gp knock-out (KO) and P-gp competent wild-type (WT) mice. Brain and plasma exposure time-courses were measured after an acute subcutaneous dose and at steady-state obtained after subcutaneous drug infusion by osmotic minipumps. Following acute dosing, the brain-to-plasma KO/WT exposure enhancement ratios ((AUCbrain ko/AUCplasma ko)/(AUCbrain WT/AUCplasma WT)) were 5.8 (levomilnacipran), 5.4 (vilazodone), 3.1 (escitalopram) and 0.9 (vortioxetine), respectively. At steady-state, assessment of Kp,uu (unbound brain concentrations/unbound plasma concentrations) revealed a restriction in the brain distribution in WT mice for all compounds except vortioxetine. Levomilnacipran exhibited the most pronounced efflux with a Kp,uu-value of 0.038 in WT mice which was increased to 0.37 in KO mice. Based on both the acute and steady-state distribution data, the results suggest that levomilnacipran, vilazodone and escitalopram are susceptible to P-gp mediated efflux at the BBB in vivo in mice, whereas vortioxetine was practically devoid of being affected by P-gp in vivo. The functional impact of the drug transport-controlling role of P-gp at the BBB was demonstrated by in vivo cortical serotonin transporter occupancy of vilazodone, which exhibited a 20-fold higher plasma EC50 in WT mice compared to KOs.

Hypophagia and induction of serotonin transporter gene expression in raphe nuclei of male and female rats after short-term fluoxetine treatment

Serotonin (5-HT) is one of the regulators of feeding in humans. Drugs acting on the serotoninergic system are used to treat bulimia nervosa and to enhance the effect of hypocaloric diets in overweight subjects. They act rapidly to normalise feeding when used to treat eating-related problems. To explore the role of the 5-HT transporter (serotonin transporter (SERT)) in the short-term action of serotonin selective reuptake inhibitor fluoxetine, rats were i.p. given the drug for five consecutive days. Acute administration of fluoxetine in male and female rats produced a strong reduction in food intake, an effect that held up when daily treatment was maintained for five consecutive days. This reduction translated into a diminution of body weight that was statistically significant in the case of the males. As a reflection of the body weight change in rats killed after the fifth daily drug injection, retroperitoneal fat pad also decreased; a diminution that was statistically significant in the case of male rats. In these conditions, plasma leptin levels of both male and female rats were lower than in untreated animals. While acute fluoxetine administration did not modify SERT gene expression, subchronic drug treatment increased the content of SERT mRNA in the midbrain raphe complex of both rat genders. These findings may contribute to explain the role of SERT in fluoxetine action on binging and as an adjunct to hypocaloric diets (AU)

Improved mapping and quantification of serotonin transporter availability in the human brainstem with the HRRT.

PURPOSE: The serotonin system is involved in many physiological functions and clinical conditions. Serotonergic neurons originate from the raphe nuclei in the brainstem, and reliable estimates of receptor/transporter availability in the raphe in vivo are thus of interest. Though positron emission tomography (PET) can be used to quantify receptor distribution in the brain, high noise levels prevent reliable estimation of radioligand binding in small regions such as the raphe. For this purpose, parametric imaging in combination with high-resolution PET systems may provide images with reduced noise levels and sufficient contrast for reliable quantification. This study examined the potential to evaluate radioligand binding in brainstem nuclei, and assessed the effect of improved resolution on the outcome measures. METHODS: For comparative purposes, radioligand binding was measured with an ECAT EXACT HR PET system (resolution about 4.5 mm FWHM) and a high-resolution research tomograph (HRRT) system (resolution about 1.5 mm FWHM). Six subjects were examined with both systems on the same day using the serotonin transporter radioligand [(11)C]MADAM. Parametric images of binding potential (BP (ND)) were obtained using a wavelet-aided approach. Regions of interest (ROIs) were delineated using a threshold-based semiautomatic delineation procedure for five brainstem structures. Regional BP (ND) values were estimated by applying the ROIs to the parametric images, and the percentage difference in BP (ND) between the systems was calculated. RESULTS: Signals for [(11)C]MADAM binding were obtained for all five brainstem structures. Overall, the HRRT provided 30-40 % higher BP (ND) values than the HR (p = 0.0017), independent of thresholds used in the ROI delineation procedure. CONCLUSION: The methodology used enabled the estimation of [(11)C]MADAM binding in the small nuclei of the brainstem. Differences in the BP (ND) values calculated using data from the two systems were mainly attributable to their differing resolutions. The estimated BP (ND) values provided lower across-subject variability than those previously obtained using compartment analysis. This procedure may therefore facilitate quantitative studies of receptor/transporter availability in the brainstem.

Impaired cognition in bipolar I disorder: the roles of the serotonin transporter and brain-derived neurotrophic factor.

BACKGROUND: Studies have proposed that cognitive deficits are present in a variety of mood states in bipolar disorder (BD). The goal of this study was to find the cognitive deficits in euthymic BD patients and to further explore possible underlying mechanisms of the deficits. METHODS: Thirty-three healthy controls (HCs) and twenty-three euthymic BD type I patients were recruited. Single photon emission computed tomography (SPECT) with (123)I-ADAM was used to image the serotonin transporter (SERT). Ten milliliters of venous blood was drawn for the measurement of brain derived neurotrophic factor (BDNF). Cognitive functions were tested included attention, memory, and executive function. RESULTS: We found that the SERT availability in both the midbrain and striatal regions was decreased in the BD patients compared with the HCs; however, the BDNF were not different between the two groups. There was no correlation between the SERT availability and the BDNF. Interestingly, there were statistically significant differences in sub-items of the facial memory test and the Wisconsin Card Sorting Test between the BD patients and the HCs, which showed that there was a cognitive deficit in the BD patients. However, the overall deficits in cognition were not significantly correlated with the SERT availability or the BDNF. LIMITATION: The effect of medications on cognitive function and BDNF should be considered. CONCLUSIONS: We replicated previous findings that showed cognitive deficits in euthymic BD patients. However, the underlying mechanism of cognitive deficits in euthymic BD patients cannot be entirely explained by SERT and BDNF.

Pharmacogenomics and antidepressant drugs.

While antidepressant pharmacotherapy is an effective treatment of depression, it still is hampered by a delayed time of onset of clinical improvement and a series of side effects. Moreover, a substantial group of patients has only limited response or fails to respond at all. One source accounting for these variations are genetic differences as currently analysed by single nucleotide polymorphisms (SNP) mapping. In recent years a number of pharmacogenetic studies on antidepressant drugs have been published. So far they mostly focused on metabolizing enzymes of the cytochrome P450 (CYP) families and genes within the monoaminergic system with compelling evidence for an effect of CYP2D6 polymorphisms on antidepressant drug plasma levels and of a serotonin transporter promoter polymorphism on clinical response to a specific class of antidepressants, the selective serotonin reuptake inhibitors. It is clear, however, that other candidate systems have to be considered in the pharmacogenetics of antidepressant drugs, such as neuropeptidergic systems, the hypothalamus-pituitary adrenal (HPA) axis and neurotrophic systems. There is recent evidence that polymorphisms in genes regulating the HPA axis have an important impact on response to antidepressants. These studies mark the beginning of an emerging standard SNP profiling system that ultimately allows identifying the right drug for the right patient at the right time.

Pharmacokinetic profile of single and repeated oral doses of MDMA in squirrel monkeys: relationship to lasting effects on brain serotonin neurons.

A large body of data indicates that (+/-)3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') can damage brain serotonin neurons in animals. However, the relevance of these preclinical data to humans is uncertain, because doses and routes of administration used in animals have generally differed from those used by humans. Here, we examined the pharmacokinetic profile of MDMA in squirrel monkeys after different routes of administration, and explored the relationship between acute plasma MDMA concentrations after repeated oral dosing and subsequent brain serotonin deficits. Oral MDMA administration engendered a plasma profile of MDMA in squirrel monkeys resembling that seen in humans, although the half-life of MDMA in monkeys is shorter (3 vs 6-9 h). MDMA was biotransformed into MDA, and the plasma ratio of MDA to MDMA was 3-5 / 100, similar to that in humans. MDMA accumulation in squirrel monkeys was nonlinear, and plasma levels were highly correlated with regional brain serotonin deficits observed 2 weeks later. The present results indicate that plasma concentrations of MDMA shown here to produce lasting serotonergic deficits in squirrel monkeys overlap those reported by other laboratories in some recreational 'ecstasy' consumers, and are two to three times higher than those found in humans administered a single 100-150 mg dose of MDMA in a controlled setting. Additional studies are needed on the relative sensitivity of brain serotonin neurons to MDMA toxicity in humans and non-human primates, the pharmacokinetic parameter(s) of MDMA most closely linked to the neurotoxic process, and metabolites other than MDA that may play a role.