Serotonin transporter binding is reduced in seasonal affective disorder following light therapy.

OBJECTIVE: To investigate the effects of light therapy on serotonin transporter binding (5-HTT BPND ), an index of 5-HTT levels, in the anterior cingulate and prefrontal cortices (ACC and PFC) during winter in seasonal affective disorder (SAD). 5-HTT BPND fluctuates seasonally to a greater extent in SAD relative to health. We hypothesized that in SAD, 5-HTT BPND would be reduced in the ACC and PFC following light therapy. METHODS: Eleven SAD participants underwent [11 C] DASB positron emission tomography (PET) scans to measure 5-HTT BPND before and after 2 weeks of daily morning light therapy. RESULTS: The primary finding was a main effect of treatment on 5-HTT BPND in the ACC and PFC (repeated-measures manova, F(2,9) = 6.82, P = 0.016). This effect was significant in the ACC (F(1,10) = 15.11 and P = 0.003, magnitude of decrease, 11.94%) and PFC (F(1,10) = 8.33, P = 0.016, magnitude of decrease, 9.13%). 5-HTT BPND also decreased in other regions assayed following light therapy (repeated-measures manova, F(4,7) = 8.54, P = 0.028) including the hippocampus, ventral striatum, dorsal putamen, thalamus and midbrain (F(1,10) = 8.02-36.94, P < 0.0001-0.018; magnitude -8.83% to -16.74%). CONCLUSIONS: These results demonstrate that light therapy reaches an important therapeutic target in the treatment of SAD and provide a basis for improvement of this treatment via application of [11 C]DASB PET.

Light therapy and serotonin transporter binding in the anterior cingulate and prefrontal cortex.

OBJECTIVE: To investigate the effects of light therapy on serotonin transporter binding (5-HTT BPND ), an index of 5-HTT levels, in the anterior cingulate and prefrontal cortices (ACC and PFC) of healthy individuals during the fall and winter. Twenty-five per cent of healthy individuals experience seasonal mood changes that affect functioning. 5-HTT BPND has been found to be higher across multiple brain regions in the fall and winter relative to spring and summer, and elevated 5-HTT BPND may lead to extracellular serotonin loss and low mood. We hypothesized that, during the fall and winter, light therapy would reduce 5-HTT BPND in the ACC and PFC, which sample brain regions involved in mood regulation. METHOD: In a single-blind, placebo-controlled, counterbalanced, crossover design, [(11) C]DASB positron emission tomography was used measure 5-HTT BPND following light therapy and placebo conditions during fall and winter. RESULTS: In winter, light therapy significantly decreased 5-HTT BPND by 12% in the ACC relative to placebo (F1,9 = 18.04, P = 0.002). In the fall, no significant change in 5-HTT BPND was found in any region across conditions. CONCLUSION: These results identify, for the first time, a central biomarker associated with the intervention of light therapy in humans which may be applied to further develop this treatment for prevention of seasonal depression.

Neuroinflammation in healthy aging: a PET study using a novel Translocator Protein 18kDa (TSPO) radioligand, [(18)F]-FEPPA.

One of the cellular markers of neuroinflammation is increased microglia activation, characterized by overexpression of mitochondrial 18kDa Translocator Protein (TSPO). TSPO expression can be quantified in-vivo using the positron emission tomography (PET) radioligand [(18)F]-FEPPA. This study examined microglial activation as measured with [(18)F]-FEPPA PET across the adult lifespan in a group of healthy volunteers. We performed genotyping for the rs6971 TS.PO gene polymorphism to control for the known variability in binding affinity. Thirty-three healthy volunteers (age range: 19-82years; 22 high affinity binders (HAB), 11 mixed affinity binders (MAB)) underwent [(18)F]-FEPPA PET scans, acquired on the High Resolution Research Tomograph (HRRT) and analyzed using a 2-tissue compartment model. Regression analyses were performed to examine the effect of age adjusting for genetic status on [(18)F]-FEPPA total distribution volumes (VT) in the hippocampus, temporal, and prefrontal cortex. We found no significant effect of age on [(18)F]-FEPPA VT (F (1,30)=0.918; p=0.346), and a significant effect of genetic polymorphism (F (1,30)=8.767; p=0.006). This is the first in-vivo study to evaluate age-related changes in TSPO binding, using the new generation TSPO radioligands. Increased neuroinflammation, as measured with [(18)F]-FEPPA PET was not associated with normal aging, suggesting that healthy elderly individuals may serve as useful benchmark against patients with neurodegenerative disorders where neuroinflammation may be present.

A randomised trial of enteric-coated nutrient pellets to stimulate gastrointestinal peptide release and lower glycaemia in type 2 diabetes.

AIMS/HYPOTHESES: Glucagon-like peptide-1 (GLP-1), an important mediator of postprandial glycaemia, could potentially be stimulated by delivering small quantities of nutrient to a long length of distal gut. We aimed to determine whether enteric-coated pellets, releasing small amounts of lauric acid throughout the ileum and colon, could reduce glycaemic responses to meals in type 2 diabetes, associated with stimulation of GLP-1. METHODS: Eligible patients, who had type 2 diabetes controlled by diet or metformin, were each studied on two occasions in a hospital setting. After an overnight fast, patients consumed 5 g active pellets (47% lauric acid by weight) or placebo with breakfast (T = 0 min) and lunch (T = 240 min), in a crossover design with order randomised by the hospital pharmacy and allocation concealed by numbered containers. Patients and investigators making measurements were blinded to the intervention. Blood was sampled frequently for blood glucose (the primary outcome) and hormone assays. RESULTS: Eight patients were randomised (four to receive either intervention first), and all completed the study without adverse effects. Blood glucose was lower after breakfast (T = 0-240 min, area under the curve (AUC) 2,075 ± 368 vs 2,216 ± 163 mmol/l × min) and lunch (T = 240-480 min, AUC 1,916 ± 115 vs 2,088 ± 151 mmol/l × min) (p = 0.02 for each) after active pellets than after placebo. Plasma GLP-1 concentrations were higher after breakfast (p = 0.08) and lunch (p = 0.04) for active pellets. While there were no differences in insulin or glucose-dependent insulinotropic polypeptide concentrations, glucagon concentrations were higher after breakfast and lunch (p = 0.002 for each) for active pellets. CONCLUSIONS/INTERPRETATION: Delivering small amounts of nutrient to the ileum and colon can stimulate substantial endogenous GLP-1 release and attenuate postprandial glycaemia. This novel approach has therapeutic potential in type 2 diabetes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000600842. FUNDING: The study was funded by Meyer Nutriceuticals.

Nanoplasma dynamics of single large xenon clusters irradiated with superintense x-ray pulses from the linac coherent light source free-electron laser.

The plasma dynamics of single mesoscopic Xe particles irradiated with intense femtosecond x-ray pulses exceeding 10(16) W/cm2 from the Linac Coherent Light Source free-electron laser are investigated. Simultaneous recording of diffraction patterns and ion spectra allows eliminating the influence of the laser focal volume intensity and particle size distribution. The data show that for clusters illuminated with intense x-ray pulses, highly charged ionization fragments in a narrow distribution are created and that the nanoplasma recombination is efficiently suppressed.

Relationship of monoamine oxidase A binding to adaptive and maladaptive personality traits.

BACKGROUND: Monoamine oxidase A (MAOA) is an important enzyme that metabolizes monoamines such as serotonin, norepinephrine and dopamine in the brain. In prefrontal cortex, low MAOA binding is associated with aggression and high binding is associated with major depressive disorder (MDD) and also risk for recurrence of depressive episodes. In rodent models, low MAOA levels are associated with increased aggression and fear conditioning, and decreased social and exploratory investigative behaviors. Our objective was to measure MAOA binding in prefrontal cortex and concurrently evaluate a broad range of validated personality traits. We hypothesized that prefrontal MAOA binding would correlate negatively with angry-hostility, a trait related to aggression/anger, and positively with traits intuitively related to adaptive investigative behavior. METHOD: Participants were aged 19-49 years, healthy and non-smoking. MAOA binding was measured with [11C]harmine positron emission tomography (PET) in prefrontal brain regions and personality traits were measured with the NEO Personality Inventory Revised (NEO PI-R). RESULTS: Prefrontal MAOA binding correlated negatively with angry-hostility (r=-0.515, p=0.001) and positively with deliberation (r=0.514, p=0.001). In a two-factor regression model, these facets explained 38% of variance in prefrontal MAOA binding. A similar relationship was found in prefrontal cortex subregions. CONCLUSIONS: We propose a new continuum describing the relationship between personality and MAOA: deliberate/thoughtful contrasting aggressive/impulsive. Additionally, the association between high MAOA binding and greater deliberation may explain why some people have moderately high levels of MAOA, although very high levels occur during MDD. In health, higher MAOA binding is associated with an adaptive personality facet.

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants.

Objectives: More than 40 drugs are available to treat affective disorders. Individual selection of the optimal drug and dose is required to attain the highest possible efficacy and acceptable tolerability for every patient.Methods: This review, which includes more than 500 articles selected by 30 experts, combines relevant knowledge on studies investigating the pharmacokinetics, pharmacodynamics and pharmacogenetics of 33 antidepressant drugs and of 4 drugs approved for augmentation in cases of insufficient response to antidepressant monotherapy. Such studies typically measure drug concentrations in blood (i.e. therapeutic drug monitoring) and genotype relevant genetic polymorphisms of enzymes, transporters or receptors involved in drug metabolism or mechanism of action. Imaging studies, primarily positron emission tomography that relates drug concentrations in blood and radioligand binding, are considered to quantify target structure occupancy by the antidepressant drugs in vivo. Results: Evidence is given that in vivo imaging, therapeutic drug monitoring and genotyping and/or phenotyping of drug metabolising enzymes should be an integral part in the development of any new antidepressant drug.Conclusions: To guide antidepressant drug therapy in everyday practice, there are multiple indications such as uncertain adherence, polypharmacy, nonresponse and/or adverse reactions under therapeutically recommended doses, where therapeutic drug monitoring and cytochrome P450 genotyping and/or phenotyping should be applied as valid tools of precision medicine.

The stalemate in food and agricultural research, teaching, and extension.

The development of leaders and colleges with the vision and ability to create an environment for both short- and long-term responses to societal concerns will be critical for the survival of these LGCAs. They will need help in escaping from old ideas, which means escaping from old organizations built on the past. A new sponsoring organization is needed to aid in this effort. With a new intellectual foundation, and the future firmly in mind, then and only then should a new national organization be instituted.

Androgens alter the tuning of electroreceptors.

Weakly electric fish possess electroreceptors that are tuned to their individual electric organ discharge frequencies. One genus, Sternopygus, displays both ontogenetic and seasonal shifts in these frequencies, possibly because of endocrine influences. Systemic treatment with androgens lowers the discharge frequencies in these animals. Concomitant with these changes in electric organ discharge frequencies are decreases in electroreceptor best frequencies; hence the close match between discharge frequency and receptor tuning is maintained. These findings indicate that the tuning of electroreceptors is dynamic and that it parallels natural shifts in electric organ discharge frequency.

Analysis of segmental phosphate absorption in intact rats. A compartmental analysis approach.

Available information supports the dominance of the proximal intestine in inorganic phosphate (Pi) absorption. However, there is no strategy for analyzing segmental Pi absorption from a spontaneously propelled meal in an intact animal. We propose a solution using compartmental analysis. After intragastric administration of a 32P-labeled Pi liquid meal containing a nonabsorbable marker, [14C]polyethylene glycol (PEG), rats were killed at 2, 10, 20, 30, 60, 120, and 240 min. The gastrointestinal tract was removed and divided into seven segments, from which 32P and [14C]PEG were recovered. Data was expressed as a percentage of the dose fed, i.e., (32P[in segment] divided by 32P[fed]) and [14C]PEG[in segment] divided by [14C]PEG[fed]), respectively. A compartmental model was constructed and the rate constants for intersegmental transit and segmental absorption were estimated. The "goodness of fit" between the simulated model and the actual data indicates the estimated rate constants reflect in vivo events. The duodenum, with the highest transit and absorption rates, accounted for a third of the total absorption. However, the terminal ileum, with a lower absorption rate but a longer transit time, absorbed an equal amount of Pi. This approach allows the analysis of the mechanism and the regulation of Pi absorption under more authentic in vivo conditions.

[Optical coherence tomography angiography (OCT­A) in rats]. / Optische-Kohärenztomographie-Angiographie (OCT­A) bei Ratten.

PURPOSE: Optical coherence tomography angiography (OCT­A) allows for the non-invasive, three-dimensional visualization of retinal and chorioidal vascular structures. In this study, this new imaging modality was evaluated in rats. METHODS: In vivo imaging in Dark Agouti rats was performed using confocal scanning laser ophthalmoscopy (cSLO) and OCT­A (Spectralis prototype, Heidelberg Engineering) after adjusting the length of the reference arm. The OCT­A en-face images were compared to conventional fluorescein angiography cSLO images. The histological examination allowed for correlation of retinal and chorioidal plexus. RESULTS: While the diagnostic device was developed for use in humans, OCT­A and cSLO imaging can be applied in rodents after only minor hardware modifications. High-resolution and contrast-enhanced images enable a depth-selective visualization of the three retinal plexus and the inner and outer chorioidal vascular networks. In comparison to fluorescein angiography (FA), OCT­A is characterized by higher resolution and more accurate three-dimensional localization of vascular structures, particularly in deep layers. A current limitation includes the relatively small area imaged by OCT­A. DISCUSSION: The recently developed OCT­A imaging technology also allows for three-dimensional detection of retinal and chorioidal vascular changes in vivo without dye injection in rodents. OCT may potentially replace invasive FA for specific questions and will be useful in animal models for research of retinal and chorioidal angiogenic processes physiologically and during pharmacological interventions.

Effect of lipase inhibition on gastric emptying of, and the glycemic and incretin responses to, an oil/aqueous drink in type 2 diabetes mellitus.

This study examined the effects of the lipase inhibitor, orlistat, on gastric emptying of, and the glycemic and incretin hormone responses to, a drink containing oil and glucose components in patients with type 2 diabetes. Seven patients (aged 58 +/- 5 yr), managed by diet alone, consumed 60 ml olive oil (labeled with 20 MBq (99m)Tc-V-thiocyanate) and 300 ml water containing 75 g glucose (labeled with 6 MBq (67)Ga-EDTA), on two occasions, with and without 120 mg orlistat, positioned in the left lateral decubitus position with their back against a gamma camera. Venous blood samples, for measurement of blood glucose and plasma insulin, glucagon-like peptide-1 and glucose-dependent insulintropic polypeptide were obtained immediately before, and after, the drink. Gastric emptying of both oil (P < 0.001) and glucose (P < 0.0005) was faster after orlistat compared with control. Postprandial blood glucose (P < 0.001) and plasma insulin (P < 0.05) were substantially greater after orlistat compared with control. In contrast, plasma glucagon-like peptide-1 (P < 0.005) and glucose-dependent insulintropic polypeptide (P < 0.05) were less after orlistat. In conclusion, inhibition of fat digestion, by orlistat, may exacerbate postprandial glycemia, as a result of more rapid gastric emptying and a diminished incretin response.

Noradrenergic dysfunction in the prefrontal cortex in depression: an [15O] H2O PET study of the neuromodulatory effects of clonidine.

BACKGROUND: Noradrenergic dysfunction has been consistently implicated in depression. Much of the evidence, though, has been indirect, such as an attenuated growth hormone response to the alpha2-adrenoceptor agonist clonidine. To more directly examine central functioning of the noradrenergic system in depression, we have used [15O] H2O positron emission tomography (PET) to measure cerebral blood flow (rCBF) in combination with clonidine as a neuromodulatory probe. METHODS: Subjects were six depressed and six healthy women, medication free and matched for age and phase of menstrual cycle. Two PET scans were acquired at baseline and two scans at 20 and 35 min following an intravenous clonidine infusion of 1.4 microg/kg while subjects performed a sustained attention task. RESULTS: The growth hormone response did not show a significant difference between groups. However, PET results revealed a difference in the right superior prefrontal cortex that was resolved as an interaction from decreased rCBF in healthy control subjects but increased rCBF in the depressed group, which was not accounted for by differences in task performance. CONCLUSIONS: This differential effect of clonidine in the right prefrontal cortex provides in vivo evidence of noradrenergic dysfunction in depression, which we postulate arises from functionally impaired presynaptic alpha2-adrenoceptors as well as regionally "supersensitive" postsynaptic cortical alpha2-adrenoceptors.

Positron emission tomography quantification of [(11)C]-DASB binding to the human serotonin transporter: modeling strategies.

[(11) C]-DASB, namely [(11) C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, is a new highly selective radioligand for the in vivo visualization of the serotonin transporter (SERT) using positron emission tomography (PET). The current study evaluates different kinetic modeling strategies for quantification of [(11)C]-DASB binding in five healthy humans. Kinetic analyses of tissue data were performed with a one-tissue (1CM) and a two-tissue (2CM) compartment model. Time-activity curves were well described by a 1CM for all regions. A 2CM model with four parameters failed to converge reliably. Reliable fits of the data were obtained only if no more than three parameters were allowed to vary. However, even then, the rate constants k(3) and k(4) were estimated with poor precision. Only the ratio k(3)/k(4) was stable. Goodness of fit was not improved by using a 2CM as compared with a 1CM. The minimal study duration required to obtain stable k(3)/k(4) estimates was 80 minutes. For routine use of [(11)C]-DASB, several simplified methods using the cerebellum as a reference region to estimate nonspecific binding were also evaluated. The transient equilibrium, the linear graphical analysis, the ratio of target to reference region, and the simplified reference tissue methods all gave binding potential values consistent with those obtained with the 2CM. The suitability of [(11)C]-DASB for research on the SERT using PET is thus supported by the observations that tissue data can be described using a kinetic analysis and that simplified quantitative methods, using the cerebellum as reference, provide reliable estimates of SERT binding parameters.

No effect of depression on [(15)O]H2O PET response to intravenous d-fenfluramine.

OBJECTIVE: Subnormal prolactin responses to the serotonin-releasing agonist fenfluramine occur in depression. Since many measures of serotonin pathology occur in depression, abnormal responses to fenfluramine may occur in brain structures other than the hypothalamic-pituitary axis. One study compared six depressed and six healthy subjects' responses to oral d,l-fenfluramine by assessing [18F]fluorodeoxyglucose uptake as detected by positron emission tomography (PET). That study showed several abnormalities within the cortex, and the authors concluded that low responsivity to d,l-fenfluramine is widespread in depression. In this study abnormalities in regional neuromodulation by serotonin in major depression were assessed with intravenous d-fenfluramine and [(15)O]H2O PET. METHOD: Changes in regional cerebral blood flow (CBF) were detected by using [(15)O]H2O PET after administration of intravenous d-fenfluramine to 13 depressed and 18 healthy women. The PET scans were done 20 and 5 minutes before and 20 and 35 minutes after d-fenfluramine administration. Differences between the depressed and healthy groups in change in regional CBF (mean postfenfluramine minus mean prefenfluramine) were analyzed by using statistical parametric mapping. RESULTS: There were no significant differences between depressed and healthy subjects; in fact, changes in regional CBF after intravenous d-fenfluramine were remarkably similar. CONCLUSIONS: Degrees of neuronal responsivity to d-fenfluramine are similar in depressed and healthy subjects. Differences between the previous and current findings may be accounted for by greater specificity of intravenous d-fenfluramine to serotonin release, timing of scans, paucity of suicidal subjects in the current study, or greater variance in regional CBF from direct vascular effects of serotonin.

Occupancy of serotonin transporters by paroxetine and citalopram during treatment of depression: a [(11)C]DASB PET imaging study.

OBJECTIVE: Selective serotonin reuptake inhibitors are commonly used to treat major depression; however, the percentage of serotonin (5-HT) transporter (5-HTT) sites occupied during clinical dosing is unknown. This study measured the proportion of 5-HTT sites blocked during paroxetine and citalopram treatment of depression and assessed the relationship between serum paroxetine levels and the proportion of 5-HTT sites blocked. METHOD: Twelve medication-free depressed patients completed a 6-week trial of either paroxetine (N=8) or citalopram (N=4). Striatal 5-HTT binding potential was measured with [(11)C]DASB and positron emission tomography, before and after 4 weeks of treatment. The binding potential is proportional to receptor density. Striatal 5-HTT binding potential was measured twice in six healthy subjects and once in 11 healthy subjects. RESULTS: A significant decrease in striatal 5-HTT binding potential was found after either treatment, compared to changes found over a 4-week period in healthy subjects. For patients treated with 20 mg/day of paroxetine (N=7), the mean proportion of 5-HTT sites occupied was 83%. For patients treated with 20 mg/day of citalopram (N=4), the mean 5-HTT occupancy was 77%. 5-HTT occupancy increased in a nonlinear relationship with serum levels of paroxetine such that a plateau of occupancy around 85% occurred for serum paroxetine levels greater than 28 microg/liter. CONCLUSIONS: During treatment with clinical doses of paroxetine or citalopram, approximately 80% of 5-HTT receptors are occupied. This change in 5-HTT binding potential is greater than the known physiological range of changes in 5-HTT binding potential but may be necessary for some therapeutic effects.

Prefrontal cortex 5-HT2 receptors in depression: an [18F]setoperone PET imaging study.

OBJECTIVE: Widespread disturbances of serotonin (5-HT) are implicated in the pathophysiology of depression. Of 5-HT receptor abnormalities reported, the most replicated finding is increased 5-HT2 receptor binding in the postmortem prefrontal cortex of depressed suicide victims. The extent to which these findings exist in depressed persons without recent suicide attempts is uncertain. The objective of this study was to evaluate 5-HT2 receptors in depressed patients who were medication-free and who had not made recent suicide attempts. METHOD: With the use of [18F]setoperone and positron emission tomography (PET), 5-HT2 receptor binding potential was assessed in 14 depressed and 19 healthy subjects. Exclusion criteria for depressed patients included use of antidepressant medication within the past 6 months, a history of suicide attempts within the past 5 years, other current axis I disorders including bipolar disorder, and the presence of psychotic symptoms. The 5-HT2 (setoperone) binding potential in the two groups of subjects was compared by analysis of covariance with age as the covariate. RESULTS: Age had a significant effect on 5-HT2 binding potential, but depression did not. The interaction of age and depression was not significant. CONCLUSIONS: The 5-HT2 binding potential is not increased in untreated depressed subjects who have not made recent suicide attempts. This negative finding does not rule out the possibility that there is a role for 5-HT2 receptors in treatment or that 5-HT2 receptors are increased in highly suicidal states.

Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression.

OBJECTIVE: Depression is commonly associated with frontal hypometabolic activity accompanied by hypermetabolism in certain limbic regions. It is unclear whether successful antidepressant treatments reverse these abnormalities or create new resting levels of metabolism. The aim of the present study was to assess the effects of successful paroxetine treatment on regional glucose metabolism in patients with major depression. METHOD: Positron emission tomography with [(18)F]fluorodeoxyglucose was performed on 13 male patients before and after 6 weeks of paroxetine therapy. Resting state scans were also acquired under similar conditions in 24 healthy male subjects for comparison. RESULTS: After successful paroxetine therapy, increased glucose metabolism occurred in dorsolateral, ventrolateral, and medial aspects of the prefrontal cortex (left greater than right), parietal cortex, and dorsal anterior cingulate. Areas of decreased metabolism were noted in both anterior and posterior insular regions (left) as well as right hippocampal and parahippocampal regions. In comparison to metabolism levels in a group of healthy volunteers, the increase in prefrontal metabolic activity represented a normalization of previously reduced metabolic activity, whereas the reduction in pregenual anterior cingulate activity represented a decrease from previously elevated metabolic levels. CONCLUSIONS: These results provide further support for a dysfunction in cortical-limbic circuitry in depression, which is at least partly reversed after successful paroxetine treatment.

The effect of paroxetine on 5-HT(2A) receptors in depression: an [(18)F]setoperone PET imaging study.

OBJECTIVE: In the cortex of animals, serotonin (5-HT) levels increase after several weeks of treatment with selective serotonin reuptake inhibitors (SSRIs). Studies using an intrasubject design to examine the effects of SSRI treatment on 5-HT(2A) receptors in the cortex of drug-free depressed patients are needed. In theory, agonist stimulation of 5-HT(2A) receptors could be relevant to SSRI treatment by promoting neuronal growth and survival as well as direct elevation of mood. The objective of this study was to evaluate the effect of 6 weeks of paroxetine treatment on 5-HT(2A) receptors in depressed patients. METHOD: After a medication-free period of at least 3 months, 19 depressed patients were treated for 6 weeks with paroxetine, 20 mg/day. The authors used [(18)F]setoperone and positron emission tomography to assess 5-HT(2A) receptor binding potential in the patients before and after treatment and in 19 age-matched healthy subjects. RESULTS: 5-HT(2A) binding potential declined with age in all cortical regions in the depressed and healthy subjects. There was a significant interaction between age and treatment effect on 5-HT(2A) binding potential in all cortical regions. Subjects aged 20 to 30 years had a 10% decrease in 5-HT(2A) binding potential after treatment, whereas subjects aged 30 to 40 had no change. No regional differences in 5-HT(2A) binding potential between depressed and healthy subjects were found. CONCLUSIONS: 5-HT(2A) receptors down-regulate in young depressed subjects after treatment with paroxetine, but this down-regulation attenuates with age. This suggests that over 6 weeks paroxetine treatment increases 5-HT agonism on 5-HT(2A) receptors in the cortex of young patients with depression.

GI transit and absorption of solid food: multiple effects of guar.

These experiments were undertaken in dogs with midintestinal fistulas to determine whether guar added to a meal of solid food would disrupt gastric sieving and give rise to maldigestion of solid food. Dogs were fed a standard meal of steak, chicken liver, bread, margarine, and water in which there was 0, 3.3, 7.5, or 15 g guar powder. The margarine or the liver contained [14C]triolein. Using an isotope ratio method, we determined how much [14C]triolein was absorbed at midintestine. We found that guar in a dose-related fashion increased the weight of chyme collected at midintestine, markedly reduced the percent of triolein absorbed by midintestine from 88 to 38%, and profoundly increased the passage to midintestine of large, poorly digestible pieces of steak and liver. The viscosity of the guar promoted the GI transit of large, poorly digestible pieces of food but also reduced absorption by other mechanisms.