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Objective This double-blind, randomised, placebo-controlled, two-part study assessed the impact of GSK2981710, a medium-chain triglyceride (MCT) that liberates ketone bodies, on cognitive function, safety, and tolerability in healthy older adults. Methods Part 1 was a four-period dose-selection study (n = 8 complete). Part 2 was a two-period crossover study (n = 80 complete) assessing the acute (Day 1) and prolonged (Day 15) effects of GSK2981710 on cognition and memory-related neuronal activity. Safety and tolerability of MCT supplementation were monitored in both parts of the study. Results The most common adverse event was diarrhoea (100% and 75% of participants in Parts 1 and 2, respectively). Most adverse events were mild to moderate, and 11% participants were withdrawn due to one or more adverse events. Although GSK2981710 (30 g/day) resulted in increased peak plasma β-hydroxybutyrate (BHB) concentrations, no significant improvements in cognitive function or memory-related neuronal activity were observed. Conclusion Over a duration of 14 days, increasing plasma BHB levels with daily administration of GSK2981710 had no effects on neuronal activity or cognitive function. This result indicates that modulating plasma ketone levels with GSK2981710 may be ineffective in improving cognitive function in healthy older adults, or the lack of observed effect could be related to several factors including study population, plasma BHB concentrations, MCT composition, or treatment duration.

Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M1 receptors play a critical role in modulating learning and memory and are highly expressed in the hippocampus. We examined the effect of GSK1034702, a potent M1 receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M1 receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M1 receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease.

The endogenous opioid system and µ-opioid receptors in particular have been demonstrated to play a fundamental role in hedonic and motivational behaviors reinforced by rewards. In healthy participants, the authors examined the multiple-dose safety, pharmacokinetic, and secondary pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being developed for treatment of disorders of compulsive consumption. Clinically relevant doses of GSK1521498 (2, 5, and 10 mg) following once-daily administration for 10 days, were well tolerated with no clinically relevant changes in vital signs, chemistry, or hematologic parameters and with a favorable neuropsychiatric profile. Following oral administration, median first time to reach maximum observed plasma concentration for GSK1521498 occurred 2 to 5 hours after dosing, with individual values ranging from 1 to 8 hours. Systemic exposure to GSK1521498 (area under the curve [0-∞] and maximum observed plasma concentration) increased in a slightly greater-than-dose-proportional manner, and steady-state plasma levels were reached within approximately 7 days. The secondary pharmacodynamic effects of GSK1521498 on cognition and pain threshold and tolerance were dose related, with mild to moderate impairments in measures of attention and reductions of pressure pain threshold and tolerance at the highest dose. These findings provide encouraging safety, tolerability, and pharmacokinetic data in support of the continued clinical development of GSK1521498.

Endogenous opioids and µ-opioid receptors have been linked to hedonic and rewarding aspects of palatable food intake. The authors examined the safety, pharmacokinetic, and pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity. In healthy participants, GSK1521498 oral solution and capsule formulations were well tolerated up to a dose of 100 mg. After single doses (10-150 mg), the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-proportional manner. GSK1521498 selectively reduced sensory hedonic ratings of high-sugar and high-fat dairy products and caloric intake of high-fat/high-sucrose snack foods. These findings provide encouraging data in support of the development of GSK1521498 for the treatment of disorders of maladaptive ingestive behavior or compulsive consumption.

An impaired capacity to filter or ‘gate’ sensory information is a core deficit in cognitive function associated with schizophrenia. These deficits have been linked in part to N-methyl-d-aspartate (NMDA) receptor dysfunction. An association between high levels of glycine, a positive allosteric modulator of the NMDA receptor, and sensorimotor gating impairments (i.e. prepulse inhibition (PPI) deficit) have been reported in animal models of schizophrenia as well as patients with schizophrenia. This study examined the acute effects of modulating the glycine site of the NMDA receptor (with high-dose glycine) on sensory gating as measured by PPI. Sixteen healthy male subjects (final sample size of 12) participated in a double-blind, placebo-controlled, crossover design in which each subject was tested under two acute treatment conditions separated by at least a 5-day washout period; placebo and 0.8 g/kg glycine. PPI was recorded 45 min post treatment using electromyography of the eye-blink response. Relative to placebo, high-dose glycine significantly impaired sensorimotor gating as demonstrated by a decrease in PPI ( t(11) = −2.983, p < 0.05). Administration of a high dose of glycine is associated with impairments in PPI supporting earlier observations in animals and patients with schizophrenia. This result, when taken together with findings in patients, suggests that high synaptic levels of glycine may have some clinically relevant detrimental effects and suggests a potential dissociation of clinical symptomatology and sensory information processing as a function of NMDA receptor modulation in schizophrenia.

Background: This study assessed the effects of two doses of glucose and a caffeine–glucose combination on mood and performance of an\ud ecologically valid, computerised multi-tasking platform.\ud Materials and methods: Following a double-blind, placebo-controlled, randomised, parallel-groups design, 150 healthy adults (mean age\ud 34.78 years) consumed drinks containing placebo, 25 g glucose, 60 g glucose or 60 g glucose with 40 mg caffeine. They completed a multitasking\ud framework at baseline and then 30 min following drink consumption with mood assessments immediately before and after the multitasking\ud framework. Blood glucose and salivary caffeine were co-monitored.\ud Results: The caffeine–glucose group had significantly better total multi-tasking scores than the placebo or 60 g glucose groups and were\ud significantly faster at mental arithmetic tasks than either glucose drink group. There were no significant treatment effects on mood. Caffeine\ud and glucose levels confirmed compliance with overnight abstinence/fasting, respectively, and followed the predicted post-drink patterns.\ud Conclusion: These data suggest that co-administration of glucose and caffeine allows greater allocation of attentional resources than\ud placebo or glucose alone. At present, we cannot rule out the possibility that the effects are due to caffeine alone Future studies should aim\ud at disentangling caffeine and glucose effects

The mesolimbic dopamine system plays a critical role in the reinforcing effects of rewards. Evidence from pre-clinical studies suggests that D₃ receptor antagonists may attenuate the motivational impact of rewarding cues. In this study we examined the acute effects of the D₃ receptor antagonist GSK598809 on attentional bias to rewarding food cues in overweight to obese individuals (n=26, BMI mean=32.7±3.7, range 27-40 kg/m²) who reported binge and emotional eating. We also determined whether individual differences in restrained eating style modulated the effects of GSK598809 on attentional bias. The study utilized a randomized, double-blind, placebo-controlled cross-over design with each participant tested following acute administration of placebo and GSK598809 (175 mg). Attentional bias was assessed by the visual probe task and modified Stroop task using food-related words. Overall GSK598809 had no effects on attentional bias in either the visual probe or food Stroop tasks. However, the effect of GSK598809 on both visual probe and food Stroop attentional bias scores was inversely correlated with a measure of eating restraint allowing the identification of two subpopulations, low- and high-restrained eaters. Low-restrained eaters had a significant attentional bias towards food cues in both tasks under placebo, and this was attenuated by GSK598809. In contrast, high-restrained eaters showed no attentional bias to food cues following either placebo or GSK598809. These findings suggest that excessive attentional bias to food cues generated by individual differences in eating traits can be modulated by D₃ receptor antagonists, warranting further investigation with measures of eating behaviour and weight loss.

The dopamine D(3) receptor is thought to be a potential target for treating compulsive disorders such as drug addiction and obesity. Here, we used functional Magnetic Resonance Imaging (fMRI) to investigate the effects the selective dopamine D(3) receptor antagonist GSK598809 on brain activation to food images in a sample of overweight and obese binge-eating subjects. Consistent with previous studies, processing of food images was associated with activation of a network of reward areas including the amygdala, striatum and insula. However, brain activation to food images was not modulated by GSK598809. The results demonstrate that D(3) receptor manipulation does not modulate brain responses to food images in overweight and obese subjects.

The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a marker of the serotonin system, although studies directly examining the relationship between acute changes in serotonin and the LDAEP have been inconsistent. Given the reported sex dichotomy in serotonin neurotransmission, this study examined if there are sex differences in the LDAEP.Data from 65 healthy participants from four independent studies were pooled, and their N1/P2 slopes were quantified.Mean N1/P2 slopes for female participants were higher than those for male participants (p 0.0001).These findings suggest that the LDAEP is modulated by sex potentially because of differences in serotonergic neurotransmission, and these differences may account for some of the inconsistent findings linking serotonin function and LDAEP.

Background The loudness dependence of the auditory evoked potential (LDAEP) has been proposed as an electrophysiological marker for assessing serotonergic function in vivo in humans, although accumulating evidence suggests that it is insensitive to acute changes in serotonergic neurotransmission. Very little is known about the sensitivity of the LDAEP to other neurotransmitter systems including the noradrenergic system. The current study examined the effects of noradrenergic modulation as well as serotonergic modulation on the LDAEP. Methods The study utilised a double-blind placebo-controlled design in which the LDAEP in 17 healthy males and females was tested following acute administration of each of citalopram (20 mg), reboxetine (4 mg) and placebo. Results Neither citalopram nor reboxetine modulated the LDAEP relative to placebo treatment (p > 0.05). Conclusion These findings suggest that the LDAEP is insensitive to acute changes in serotonergic or noradrenergic neurotransmission and thus is a poor pharmacodynamic marker of these systems. Copyright # 2010 John Wiley & Sons, Ltd.

Schizophrenia is commonly associated with impairments in pre-attentive change detection, as represented by reduced mismatch negativity (MMN). While the neurochemical basis of MMN has been linked to N-methyl-d-aspartic acid (NMDA) receptor function, the roles of the dopaminergic and/or the serotonergic systems are not fully explored in humans. The aim of the present study was to investigate the effects of acutely depleting dopamine (DA) and serotonin (5-hydroxytryptamine, 5-HT) alone or simultaneously by depleting their amino acid precursors on MMN in healthy participants. Sixteen healthy male subjects participated in a double-blind, placebo-controlled, cross-over design in which each subject’s duration MMN was assessed under four acute treatment conditions separated by a 5-day washout period: balanced amino acid control (no depletion), tyrosine/phenylalanine depletion (to reduce DA neurotransmission), tryptophan depletion (to reduce 5-HT neurotransmission) and tryptophan/tyrosine/phenylalanine depletion (to reduce DA and 5-HT neurotransmission simultaneously). Acute depletion of either DA and 5-HT alone or simultaneously had no effect on MMN. These findings suggest that modulation of the dopaminergic and serotonergic systems acutely does not lead to changes in MMN.

Objective This study examined sensory and cognitive processing in adolescents, young adults and older adults, when exposed to 2nd (2G) and 3rd (3G) generation mobile phone signals. Methods Tests employed were the auditory 3-stimulus oddball and the N-back. Forty-one 13–15year olds, forty-two 19–40year olds and twenty 55–70year olds were tested using a double-blind cross-over design, where each participant received Sham, 2G and 3G exposures, separated by at least 4days. Results 3-Stimulus oddball task: Behavioural : accuracy and reaction time of responses to targets were not affected by exposure. Electrophysiological : augmented N1 was found in the 2G condition (independent of age group). N-back task: Behavioural : the combined groups performed less accurately during the 3G exposure (compared to Sham), with post hoc tests finding this effect separately in the adolescents only. Electrophysiological : delayed ERD/ERS responses of the alpha power were found in both 3G and 2G conditions (compared to Sham; independent of age group). Conclusion Employing tasks tailored to each individual's ability level, this study provides support for an effect of acute 2G and 3G exposure on human cognitive function. Significance The subtlety of mobile phone effect on cognition in our study suggests that it is important to account for individual differences in future mobile phone research.

Serotonergic (SSRI) and noradrenergic (NRI) antidepressants modulate biases in emotional processing such that perceptual bias is shifted away from negative and towards positive emotional material. However, the effects of serotonergic and noradrenergic modulation on the temporal course (occurring in milliseconds) of emotional processing, and in particular, the rapid physiological changes associated with the different stages of emotional processing, are unknown.The current study assessed the effects of acute serotonergic (i.e. with citalopram) and noradrenergic (i.e. with reboxetine) augmentation on event-related potential (ERP) measures associated with 'structural encoding' (N170) and emotion expression decoding (N250 and late positive potential [LPP]) for positive (happy) and negative (sad) facial stimuli relative to neutral facial stimuli.This study employed a double-blind, placebo-controlled, cross-over design in which 12 healthy male participants completed a facial expression recognition task tested under three acute conditions: (a) placebo, (b) citalopram (20 mg) and (c) reboxetine (4 mg).Both citalopram and reboxetine had no effect on the N170 ERP component associated with structural encoding, but potentiated the N250 associated with happy (relative to neutral) emotional facial expression decoding. Both drugs had no valence effects on later ERP measures of emotion expression decoding (LPP).Citalopram and reboxetine have selective effects on the temporal course of emotional processing with evidence to suggest specific effects on emotion expression decoding of positive (happy) emotional facial stimuli as evidenced by changes in the attention-modulated N250 but not structural encoding. These findings provide physiological evidence that antidepressants may shift perceptual biases in emotional processing away from negative and towards positive stimuli.

Objective The underlying effect of serotonergic neurotransmission has been implicated in several psychiatric disorders. The inability to routinely and non-invasively determine the integrity of the serotonergic system in vivo has limited our understanding of disorders with a putative serotonergic abnormality. The loudness dependence of the auditory evoked potential (LDAEP) has been proposed as a reliable measure of central serotonin function in humans. While animal studies suggest that the LDAEP is sensitive to changes in central serotonin neurotransmission, evidence in humans has been indirect and inconsistent. The aim of this study was to assess the sensitivity of the LDAEP to acute augmentation in central serotonergic neurotransmission in humans. Methods The study used a double-blind, placebo-controlled cross-over design, in which healthy subjects were tested under four acute treatment conditions, with pharmacologically equivalent single doses of placebo, escitalopram (10 mg), citalopram (20 mg) and sertraline (50 mg) to examine the direct effect of acute enhancement of synaptic serotonin on the LDAEP. Furthermore, the outcome of the serotonergic modulatory effects on the LDAEP was also examined using two methods (dipole source analysis (DSA) vs. scalp analysis). Results Escitalopram, citalopram and sertraline had no effects on the LDAEP and were independent of the analysis method used. Conclusion These findings question the sensitivity of the LDAEP to acute changes in serotonin neurotransmission and its validity as a reliable measure of central serotonin function in humans. Copyright © 2008 John Wiley & Sons, Ltd.

Background The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a possible in vivo measure of central serotonin function. However, more recent studies suggest that the LDAEP may be modulated by multiple neuromodulatory systems in addition to the serotonergic system. Accordingly we further examined the effects of selective serotonin, dopamine and simultaneous serotonin and dopamine depletion on the LDAEP in healthy subjects. Methods The study employed a placebo-controlled, double-blind, cross over design. Fourteen subjects were tested under four acute treatment conditions: placebo (balanced amino acid drink), tryptophan (serotonin) depletion (ATD), tyrosine/phenylalanine (dopamine) depletion (ATPD) and combined tryptophan/tyrosine/phenylalanine (serotonin and dopamine) depletion (CMD). Testing was conducted 5.5 h post-depletion and changes in the amplitude of the N1/P2 at varying intensities (60, 70, 80, 90, 100 dB) were examined at CZ. Results Greater than 80% plasma precursor depletion was achieved across all conditions. Despite significant depletion of monoamine precursors, ATD, (p = 0.318), ATPD (p = 0.061) and CMD (p = 0.104) had no effects on the LDAEP (60–100 dB). Conclusion Acute serotonin and dopamine depletion did not modulate the LDAEP. This finding adds support to growing evidence that the LDAEP is insensitive to acute changes in serotonin and dopamine neurotransmission. Copyright © 2008 John Wiley & Sons, Ltd.

N-methyl-D-aspartate (NMDA) receptors play an important role in learning and memory. Targeting the glycine modulatory site of the NMDA receptor has been suggested as a therapeutic strategy to improve cognition, although findings have not been convincing. We used the Cognitive Drug Research computerised assessment system to examine the effects of high-dose glycine on a number of cognitive processes in healthy young subjects. The study was a randomised placebo controlled repeated measures design in which each subject received acute placebo or glycine (0.8 g/kg) orally, with treatment conditions separated by a 5-day washout period. No significant effects of glycine were found on measures of working memory, declarative memory, attention or perceptual processing. These findings, together with those of previous studies, cast doubt over the ability of acute high-dose glycine to improve cognitive function in healthy subjects and suggest that the optimum dose of glycine for improving cognition may vary between different populations, possibly due to differences in endogenous glycine levels and the functional status of NMDA receptors.

Schizophrenia is associated with impairments of sensorimotor and sensory gating as measured by prepulse inhibition (PPI) of the acoustic startle response and P50 suppression of the auditory event-related potential respectively. While serotonin and dopamine play an important role in the pathophysiology and treatment of schizophrenia, their role in modulating PPI and P50 suppression in humans is yet to be fully clarified. To further explore the role of serotonin and dopamine in PPI and P50 suppression, we examined the effects of acute tryptophan depletion (to decrease serotonin) and acute tyrosine/phenylalanine depletion (to decrease dopamine) on PPI and P50 suppression in healthy human participants. In addition, we also examined for the first time, the effects of simultaneous serotonin and dopamine depletion (ie combined monoamine depletion) on PPI and P50 suppression. The study was a double-blind, placebo-controlled cross-over design in which 16 healthy male participants completed the PPI and P50 paradigms under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/phenylalanine/tryptophan depletion (combined monoamine depletion). Selective depletion of dopamine had no significant effect on either PPI or P50 suppression, whereas selective serotonin depletion significantly disrupted PPI, but not P50 suppression. Finally, the simultaneous depletion of both serotonin and dopamine resulted in significant reduction of both PPI and P50 suppression. We suggest these results can be explained by theories relating to optimal levels of monoaminergic neurotransmission and synergistic interactions between serotonergic and dopaminergic systems for normal ‘gating’ function. These findings suggest that a dysfunction in both serotonin and dopamine neurotransmission may, in part, be responsible for the gating deficits observed in schizophrenia, and their normalization following administration of atypical antipsychotic drugs.

Schizophrenia is commonly associated with impairments in pre-attentive change detection as represented by reduced mismatch negativity (MMN). The neurochemical basis of MMN has been linked to N-methyl-d-aspartate (NMDA) receptor function. Glycine augments NMDA receptor function via stimulation of the glycine modulatory site of the NMDA receptor and has been shown to effectively reduce negative symptoms in schizophrenia. However, no study has investigated the possible effects of high-dose glycine on MMN. Further, the physiological consequences of administering high-dose glycine in subjects with normal NMDA receptor function are unknown. The aim of the present project was to investigate the acute effects of a single large dose of glycine on the human MMN in healthy subjects. Sixteen healthy male subjects participated in a double blind, placebo-controlled, crossover design in which each subject was tested under two acute treatment conditions separated by a 1-week washout period; placebo and 0.8 g/kg glycine. The subjects were exposed to a duration-MMN paradigm with 50-ms standard tones (91%) and 100-ms deviant tones (9%). The results showed that glycine significantly attenuated duration MMN amplitude at frontal electrodes. There was no effect of glycine on MMN latencies or on amplitudes or latencies of N1, N2 and P3a. These findings suggest that an acute high dosage of glycine attenuates MMN in healthy controls, raising the possibility that optimal effects of glycine and other glycine agonists may depend on the integrity of the NMDA receptor system.

The loudness dependence of the auditory evoked Potential (LDAEP) has been suggested to be a putative marker of central serotonin function, with reported abnormalities in clinical disorders presumed to reflect serotonin dysfunction. Despite considerable research, very little is known about the LDAEP’s sensitivity to other neurotransmitter systems. Given the role of N-methyl-d-aspartate (NMDA) receptors in modulating pyramidal cell activity in cortico-cortico and thalamo-cortical loops, we examined the effect of targeting the glycine modulatory site of the NMDA receptor with high-dose glycine on the LDAEP in healthy subjects. The study was a double-blind, placebo-controlled repeated-measures design in which 14 healthy participants were tested under two acute treatment conditions, placebo and oral glycine (0.8 g/kg). Changes in the amplitude of the N1/P2 at varying intensities (60, 70, 80, 90, 100 dB) were examined at CZ. Compared to placebo, high-dose glycine induced a weaker LDAEP (a pronounced decrease in the slope of the N1/P2 with increasing tone loudness; p

Schizophrenia is associated with impairments of attentional control on classic experimental paradigms such as the Stroop task. However, at a basic level the neurochemical mechanisms that may be responsible for such impairments are poorly understood. In this study, we sought to investigate the influence of brain monoamine function on Stroop task performance in healthy participants using the established methods of acute dietary serotonin, dopamine, and combined monoamine depletion. The study was a double-blind placebo controlled design in which 12 healthy male participants completed the Stroop task under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/phenylalanine/tryptophan depletion (combined monoamine depletion). Decreased Stroop interference indicating improved attentional control was observed after both tryptophan depletion and tyrosine/phenylalanine depletion, while there was no significant change in interference after combined monoamine depletion. Findings suggest that reduced tonic dopamine or serotonin activity within specific neural circuits (such as the striatum, anterior cingulate, or prefrontal cortex) may play a critical role in attentional control, possibly by improving gating of information via reducing noise in monoaminergic systems. These findings enhance our understanding of the neurochemical basis of attentional control and the possible cause of attentional control deficits in schizophrenia.

The Loudness Dependence of the Auditory Evoked Potential (LDAEP) has been suggested as a reliable measure of central serotonin function in humans; however, its specificity for the serotonin system remains a topic of debate, with possible modulation of this purported serotonin marker by other neurotransmitters, including dopamine.We examined the effect of dopaminergic modulation on the LDAEP using the D1/D2/D3 dopamine receptor agonist pergolide and the D2/D3 agonist bromocriptine.The study was a double-blind, placebo-controlled repeated-measures design in which healthy participants were tested under three acute treatment conditions: placebo, bromocriptine (2.5 mg), and pergolide (0.1 mg). Changes in the amplitude of the N1/P2 at intensities (60, 70, 80, 90, and 100 dB) were examined at C Z.Acute stimulation of D1/D2/D3 receptors with pergolide and D2/D3 receptors with bromocriptine in comparison with placebo had no effect on the LDAEP.These findings indicate that acute stimulation of dopamine D1, D2, and D3 receptors does not modulate the LDAEP in humans. Although the findings suggest that the LDAEP may not be modulated by acute changes in dopamine neurotransmission, further studies are needed to fully characterize its dopaminergic sensitivity.

The loudness dependence of the auditory evoked potential (LDAEP) has been suggested as a reliable measure of central serotonin function in humans. The most convincing evidence for a direct relationship between serotonergic function and LDAEP to date has come from animal studies, while evidence in humans has been circumstantial and inconsistent. In the current study, we examine the direct effect of serotonergic modulation with the selective serotonin reuptake inhibitor (SSRI) citalopram on the LDAEP. The study was a double-blind placebo controlled design in which healthy participants were tested under two acute treatment conditions: placebo and citalopram (20 mg). Enhancement of serotonin function with citalopram in comparison to placebo decreased the slope of the LDAEP (i.e. weaker LDAEP). The findings provide direct evidence in humans, of a relationship between central serotonin function and the LDAEP, supporting findings previously observed in animals and clinical populations. Together the results provide further support for the validity of the LDAEP as a non-invasive in vivo measure of central serotonin function in humans.