Sympathetic dysfunction is associated with worse fatigue and early and subtle symptoms in heart failure: an exploratory sex-stratified analysis.

AIMS: Physical symptoms impact patients with heart failure (HF) despite treatment advancements; however, our understanding of the pathogenic mechanisms underlying HF symptoms remains limited, including sex differences therein. The objective of this study was to quantify associations between sympathetic markers [norepinephrine (NE) and 3,4-dihydroxyphenylglycol (DHPG)] and physical symptoms in patients with HF and to explore sex differences in these associations. METHODS AND RESULTS: We performed a secondary analysis of combined data from two studies: outpatients with HF (n = 111), and patients prior to left ventricular assist device implantation (n = 38). Physical symptoms were measured with the Heart Failure Somatic Perception Scale (HFSPS) dyspnoea and early/subtle symptom subscales and the Functional Assessment in Chronic Illness Therapy Fatigue Scale (FACIT-F) to capture dyspnoea, early symptoms of decompensation, and fatigue. Norepinephrine and DHPG were measured with high-performance liquid chromatography with electrochemical detection. Multivariate linear regression was used to quantify associations between symptoms and sympathetic markers. The sample (n = 149) was 60.8 ± 15.7 years, 41% women, and 71% non-ischaemic aetiology. Increased plasma NE and NE:DHPG ratio were associated with worse FACIT-F scores (P = 0.043 and P = 0.013, respectively). Increased plasma NE:DHPG ratio was associated with worse HFSPS early/subtle symptoms (P = 0.025). In sex-stratified analyses, increased NE:DHPG ratio was associated with worse FACIT-F scores (P = 0.011) and HFSPS early/subtle scores (P = 0.022) among women but not men. CONCLUSION: In patients with HF, sympathetic dysfunction is associated with worse fatigue and early/subtle physical symptoms with associations stronger in women than men.

Plasma monoamines change under dopamine supersensitivity psychosis in patients with schizophrenia: A comparison with first-episode psychosis.

BACKGROUND: Patients with first-episode psychosis respond well to initial antipsychotic treatment, but among patients experiencing a relapse of psychosis, the response rate falls to approximately 30%. The mechanism of this discrepancy has not been clarified, but the development of dopamine supersensitivity psychosis with the underlying up-regulation of post-synaptic dopamine D2 receptors could be involved in this lesser response. It is uncertain whether elevated dopamine synthesis and release occurs in patients with dopamine supersensitivity psychosis, in contrast to those with first-episode psychosis. PATIENTS AND METHODS: We examined a first-episode psychosis group (n=6) and a chronic schizophrenia group, i.e. patients experiencing relapse (n=23) including those who relapsed due to dopamine supersensitivity psychosis (n=18). Following the initiation of treatment, we measured the patients' blood concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylglycol at two weeks and four weeks after the baseline measurements. RESULTS: The first-episode psychosis group tended to show decreased homovanillic acid, accompanied by an improvement of symptoms. The chronic schizophrenia group showed no alteration of homovanillic acid or 3-methoxy-4-hydroxyphenylglycol over the treatment period. These results were the same in the dopamine supersensitivity psychosis patients alone. CONCLUSIONS: Our findings suggest that unlike first-episode psychosis, the release of dopamine from presynaptic neurons did not increase in relapse episodes in the patients with dopamine supersensitivity psychosis. This indirectly indicates that the development of supersensitivity of post-synapse dopamine D2 receptor is involved in relapse in dopamine supersensitivity psychosis patients.

Plasma levels of 3-methoxy-4-hydroxyphenylglycol levels, number of hospitalization and cognitive function predicts the cognitive effect of atypical antipsychotic monotherapy in patients with acute schizophrenia.

Although the effects of atypical antipsychotics with regard to improving neurocognitive function are not sufficiently high. The present study applied an atypical antipsychotic monotherapy for patients with acute schizophrenia to (1) examine the percentage of patients who respond well to this treatment, (2) explore the factors that predict response (e.g. the improvement of neurocognition), and (3) identify the factors associated with improved neurocognitive function. We studied 40 patients with acute schizophrenia who had received atypical antipsychotic monotherapy for 24 weeks. The following parameters were evaluated at baseline and 24 weeks after the start of treatment: psychotic symptoms, neurocognitive function, and blood biological markers including homovanillic acid, 3-methoxy-4-hydroxyphenylglycol, and brain-derived neurotrophic factor. Marked improvements in neurocognitive function were noted in 7.5%-25% of patients. The factors that significantly predicted neurocognitive function improvement were the frequency of hospitalization (verbal memory and verbal fluency), 3-methoxy-4-hydroxyphenylglycol (verbal fluency and executive function), and verbal memory (working memory). Approximately 20% of the patients showed good response to treatment with antipsychotics. Frequency of hospitalization, 3-methoxy-4-hydroxyphenylglycol level, and other parameters predicted responsiveness to these drug therapies. Thus, it might be useful to apply these factors to predict responses to treatment.

Endocrine responses during CPAP withdrawal in obstructive sleep apnoea: data from two randomised controlled trials.

The aim of this investigation was to elucidate the effect of CPAP withdrawal on neurometabolic and cardiometabolic markers in patients with obstructive sleep apnoea. We evaluated 70 patients (mean age 61±10 years, 82% men) treated with CPAP in two 2-week, parallel, randomised controlled trials. CPAP withdrawal resulted in elevated 3,4-dihydroxyphenylglycol, norepinephrine and cortisol after 2 weeks of CPAP withdrawal; however, no statistically significant changes of the renin-angiotensin-aldosterone system (RAAS) determinants were documented. In summary, CPAP withdrawal may be more prominently linked to short-term increases in sympathetic activation than hypothalamic-pituitary-adrenal axis or RAAS activation. ClinicalTrials.gov Identifier: NCT02493673 and NCT02050425.

LC-MS/MS method for quantification of 3,4-dihydroxyphenylglycol, a norepinephrine metabolite in plasma and brain regions.

Aim: To evaluate suitability of the LC-MS/MS method to quantify 3,4-dihydroxyphenylglycol (DHPG) that is used as a biomarker for monoamine oxidase (MAO) inhibition. Methods: DHPG was extracted using alumina basic cartridges and quantified on a triple quadrupole mass spectrometer using negative electrospray ionization, without the use of derivatization reagents. Results: Modulation of DHPG levels was observed following administration of selective and nonselective MAO inhibitors and results were in correlation with historical MAO inhibition potential of compounds. Conclusion: The proposed method is sensitive enough to measure plasma DHPG levels and DHPG can be used as a biomarker to assess MAO inhibition potential of new therapeutic agents.

Sympathetic Markers are Different Between Clinical Responders and Nonresponders After Left Ventricular Assist Device Implantation.

BACKGROUND: Clinical response to left ventricular assist devices (LVADs), as measured by health-related quality of life, varies among patients after implantation; however, it is unknown which pathophysiological mechanisms underlie differences in clinical response by health-related quality of life. OBJECTIVE: The purpose of this study was to compare changes in sympathetic markers (ß-adrenergic receptor kinase-1 [ßARK1], norepinephrine [NE], and 3,4-dihydroxyphenylglycol [DHPG]) between health-related quality of life clinical responders and nonresponders from pre- to post-LVAD implantation. METHODS: We performed a secondary analysis on a subset of data from a cohort study of patients from pre- to 1, 3, and 6 months after LVAD implantation. Clinical response was defined as an increase of 5 points or higher on the Kansas City Cardiomyopathy Questionnaire Clinical Summary score from pre- to 6 months post-LVAD implantation. We measured plasma ßARK1 level with an enzyme-linked immunosorbent assay and plasma NE and DHPG levels with high-performance liquid chromatography with electrochemical detection. Latent growth curve modeling was used to compare the trajectories of markers between groups. RESULTS: The mean (SD) age of the sample (n = 39) was 52.9 (13.2) years, and most were male (74.4%) and received LVADs as bridge to transplantation (69.2%). Preimplantation plasma ßARK1 levels were significantly higher in clinical responders (n = 19) than in nonresponders (n = 20) (P = .001), but change was similar after LVAD (P = .235). Preimplantation plasma DHPG levels were significantly lower in clinical responders than in nonresponders (P = .002), but the change was similar after LVAD (P = .881). There were no significant differences in plasma NE levels. CONCLUSIONS: Preimplantation ßARK1 and DHPG levels are differentiating factors between health-related quality of life clinical responders and nonresponders to LVAD, potentially signaling differing levels of sympathetic stimulation underlying clinical response.

Measurement of plasma norepinephrine and 3,4-dihydroxyphenylglycol: method development for a translational research study.

OBJECTIVE: Norepinephrine (NE), a sympathetic neurotransmitter, is often measured in plasma as an index of sympathetic activity. To better understand NE dynamics, it is important to measure its principal metabolite, 3,4-dihydroxyphenylglycol (DHPG), concurrently. Our aim was to present a method, developed in the course of a translational research study, to measure NE and DHPG in human plasma using high performance liquid chromatography with electrochemical detection (HPLC-ED). RESULTS: After pre-purifying plasma samples by alumina extraction, we used HPLC-ED to separate and quantify NE and DHPG. In order to remove uric acid, which co-eluted with DHPG, a sodium bicarbonate wash was added to the alumina extraction procedure, and we oxidized the column eluates followed by reduction because catechols are reversibly oxidized whereas uric acid is irreversibly oxidized. Average recoveries of plasma NE and DHPG were 35.3 ± 1.0% and 16.3 ± 1.1%, respectively, and there was no detectable uric acid. Our estimated detection limits for NE and DHPG were approximately 85 pg/mL (0.5 pmol/mL) and 165 pg/mL (0.9 pmol/mL), respectively. The measurement of NE and DHPG in human plasma has wide applicability; thus, we describe a method to quantify plasma NE and DHPG in a laboratory setting as a useful tool for translational and clinical research.

A polymorphism in the noradrenaline transporter gene is associated with increased blood pressure in patients with resistant hypertension.

OBJECTIVES: Noradrenaline released from sympathetic nerves is rapidly inactivated via the action of the noradrenaline transporter (NET). We aimed to determine whether a single nucleotide polymorphism (SNP) in the NET gene, rs7194256, was associated with blood pressure and plasma noradrenaline concentration in patients with resistant hypertension. METHODS: Ninety-two consecutive patients with resistant hypertension participated in this study (age 62 ±â€Š1.3 years, BMI 32 ±â€Š0.6 kg/m, mean ±â€ŠSEM). Blood pressure was assessed using 24-h ambulatory blood pressure monitoring. Genotyping of rs7194256 (C/T) was performed using a predeveloped TaqMan SNP Genotyping Assay. Plasma catecholamines were analyzed using high-performance liquid chromatography. RESULTS: There were no differences in anthropometric measures between those carrying a T allele or the CC genotype. Patients carrying a T allele had significantly higher SBP: 24-h mean 148 ±â€Š2.6 vs. 140 ±â€Š2.4; 24-h max 189 ±â€Š3.2 vs. 179 ±â€Š2.6; 24-h min 114 ±â€Š3.0 vs. 105 ±â€Š2.3; night mean 141 ±â€Š3.0 vs. 131 ±â€Š2.5; night max 170 ±â€Š3.6 vs. 159 ±â€Š3.1; night min 118 ±â€Š3.4 vs. 109 ±â€Š2.4 (all P < 0.05). T-allele carriers had a significantly higher arterial noradrenaline concentration: 573 ±â€Š53 vs. 377 ±â€Š35 pg/ml (P = 0.002) and lower ratio of the intraneuronal noradrenaline metabolite, 3,4-dihydroxyphenylglycol, to noradrenaline (3.01 ±â€Š0.4 vs. 4.08 ±â€Š0.3 pg/ml; P = 0.024). CONCLUSION: A SNP in the NET gene in patients with resistant hypertension is associated with higher plasma noradrenaline concentration and elevated SBP. Impaired NET function may be a contributor to the pronounced activation of the sympathetic nervous system characteristic of patients with resistant hypertension.

Monoaminergic Markers Across the Cognitive Spectrum of Lewy Body Disease.

BACKGROUND: Lewy body disorders, including Parkinson's disease (PD), Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB), are characterized by profound central and peripheral monoaminergic dysfunction. OBJECTIVE: To investigate whether these alterations depend on dementia status, we measured cerebrospinal fluid (CSF) and serum monoamine and metabolite levels across subgroups of the cognitive spectrum, and evaluated their marker potential afterwards. METHODS: In total, 153 subjects were included, of which 43 healthy controls (HC), 28 PD patients with normal cognition (PD-NC), 26 patients with PD and mild cognitive impairment (PD-MCI), 18 PDD patients, and 38 DLB patients. The levels of monoamines and metabolites in paired CSF and serum samples were analyzed applying reversed-phase high-performance liquid chromatography with electrochemical detection. RESULTS: Firstly, when comparing subgroups, CSF 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were found lowest in HC and PD-NC groups and significantly higher in PDD/DLB patients. In addition, CSF 5-hydroxyindoleacetic acid (5-HIAA) levels differed significantly between HC and PD-MCI/PDD, and DLB patients (P≤0.001), but not between HC and PD-NC patients. Secondly, when performing logistic regression, it was shown that particularly CSF/serum MHPG levels and the serum MHPG to noradrenaline (NA) ratio effectively differentiated between HC and (non-)pooled PD subgroups (AUC = 0.914-0.956), and PDD and DLB patients (AUC = 0.822), respectively. Furthermore, CSF 5-HIAA was the most discriminative parameter to differentiate between PD-NC and PD-MCI (AUC = 0.808), and, PD-NC and PDD subgroups (AUC = 0.916). CONCLUSIONS: Our data revealed that especially alterations of the noradrenergic neurotransmitter system could distinguish between Lewy body disorder subtypes, pinpointing CSF/serum MHPG and NA as potential stage markers across the cognitive spectrum.

Blood Biomarkers Predict the Cognitive Effects of Aripiprazole in Patients with Acute Schizophrenia.

Aripiprazole has been reported to exert variable effects on cognitive function in patients with schizophrenia. Therefore, in the present study, we evaluated biological markers, clinical data, and psychiatric symptoms in order to identify factors that influence cognitive function in patients with schizophrenia undergoing aripiprazole treatment. We evaluated cognitive function in 51 patients with schizophrenia using Brief Assessment of Cognition in Schizophrenia (BACS), as well as background information, psychiatric symptoms, plasma catecholamine metabolites-homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG)-, and serum brain-derived neurotrophic factor (BDNF). Multivariate analyses were performed in order to identify factors independently associated with cognitive function. Brain-derived neurotrophic factor levels, number of hospitalizations, and MHPG levels were associated with verbal memory and learning. Total hospitalization period and MHPG levels were associated with working memory. Age at first hospitalization and education were associated with motor speed. The number of hospital admissions, Positive and Negative Syndrome Scale negative subscale scores (PANSS-N), MHPG levels, BDNF levels, and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS) scores were associated with verbal fluency. Homovanillic acid and MHPG levels, duration of illness, and PANSS-N scores were associated with attention and processing speed. Brain-derived neurotrophic factor and MHPG levels were associated with executive function. These results suggest that treatment of psychiatric symptoms and cognitive dysfunction may be improved in patients treated with aripiprazole by controlling for these contributing factors.

Relationships between serum brain-derived neurotrophic factor, plasma catecholamine metabolites, cytokines, cognitive function and clinical symptoms in Japanese patients with chronic schizophrenia treated with atypical antipsychotic monotherapy.

OBJECTIVES: Catecholamines, brain-derived neurotrophic factor (BDNF) and cytokines may be involved in the pathophysiology of schizophrenia. The aim of this study was to examine the associations between serum BDNF levels, plasma catecholamine metablolites, cytokines and the cognitive functions of patients with schizophrenia treated with atypical antipsychotic monotherapy. METHODS: One hundred and forty-six patients with schizophrenia and 51 age- and sex-matched healthy controls were examined for peripheral biological markers and neurocognitive test. RESULTS: There were positive correlations between serum BDNF levels and scores for verbal memory and attention and processing speed as well as between serum BDNF levels and negative symptoms. Furthermore, there was a negative correlation between the plasma homovanillic acid (HVA) level and motor function and a positive correlation between the plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) level and attention and processing speed. There were no significant correlations between interleukin-6 or tumour necrosis factor alpha and cognitive function. Moreover, there were no significant correlations between the plasma levels of HVA, MHPG, cytokines and clinical symptoms. CONCLUSIONS: Serum BDNF levels are positively related to the impairment of verbal memory and attention, plasma HVA levels are positively related to motor function, and plasma MHPG levels are positively related to attention in patients with schizophrenia.

Neuroanatomic pathways associated with monoaminergic dysregulation after stroke.

OBJECTIVE: We examined the complex relationship between lesion location, symptoms of depression (affective and apathetic), and monoamine dysfunction after stroke. METHODS: Magnetic resonance imaging was performed on 48 post-stroke patients that had been assessed for affective and apathetic symptoms using the Hospital Anxiety and Depression Scale and the Apathy Scale, respectively. Noradrenalin (NA), dopamine (DA), their metabolites, and a metabolite of serotonin (5-HT) were measured using 24-h urine samples, and 5-HT and 3-methoxy-4-hydroxyphenylglycol were measured using blood samples. We developed a statistical parametric map that displayed the associations between lesion location and both positive and negative alterations of monoamines and their metabolites. RESULTS: Multivariate analysis indicated that basal ganglia lesions and 5-HT showed relationships with affective symptoms, whereas homovanillic acid was related to apathetic symptoms. Univariate analysis showed no such relationships. However, decreases in NA and DA and increases in NA and DA turnover were related to lesions in the brainstem, whereas increases in NA and DA as well as decreases in NA and DA turnover were related to cortical and/or striatum lesions. 5-HT turnover data showed a pattern opposite to that seen for NA and DA turnover. CONCLUSIONS: Monoaminergic neuronal pathways are controlled by both receptor-mediated feedback mechanisms and turnover; thus, depletion of monoamines is not the only cause of depression and apathy. Moreover, the monoamine neuronal network might be divided into two branches, catecholamine (NA and DA) and 5-HT, both of which are anatomically and functionally interconnected and could respectively influence apathetic and affective symptoms of depression.

Dihydroxyphenylglycol as a Biomarker of Norepinephrine Transporter Inhibition by Atomoxetine: Human Model to Assess Central and Peripheral Effects of Dosing.

To assess the primary metabolite of norepinephrine, 3,4-dihydroxyphenylglycol (DHPG), as a sensitive biomarker for norepinephrine transporter (NET) function and the relationship of DHPG measured peripherally and centrally, NET was antagonized with 80 mg/d atomoxetine for 18 days. Twelve healthy subjects were treated with atomoxetine in an open-label, multiple-dose exploratory study. Plasma atomoxetine reached steady state by day 6, and the pharmacokinetic results demonstrated availability of atomoxetine to the central nervous system. The cerebrospinal fluid (CSF)/plasma ratios of atomoxetine based on area under concentration-time curve from 0 to 12 hours postdose (AUC0-12), maximum concentration (Cmax), and predose were 0.3%, 0.2%, and 11%, respectively. Plasma from atomoxetine-treated subjects (ex vivo) significantly inhibited radioligand binding to human NET (P < 0.001) only 1 hour after dosing. Plasma DHPG and DHPG/norepinephrine (ratio) during repeated posture tests were reduced significantly (P < 0.001) on day 5 and stayed significantly reduced up to 1 day after treatment. In CSF, both DHPG and the ratio were significantly reduced (P < 0.001) on day 18. Urine results showed significant decreases for both DHPG and the ratio (P = 0.010 to P < 0.001). Brain-derived neurotrophic factor in CSF was lesser than the limits of detection. The findings suggest that NET blockade can be assessed with DHPG concentration or with the ratio in plasma, CSF, and urine. The data suggest that DHPG is a useful biomarker to proactively assess the pharmacological activity of compounds intended to inhibit NET activity within the brain. The study shows that CSF is a medium for early identification and quantification of biomarkers useful in assessing novel neuroscience targets.

Acute effects of breaking up prolonged sitting on fatigue and cognition: a pilot study.

OBJECTIVES: To compare the acute effects of uninterrupted sitting with sitting interrupted by brief bouts of light-intensity walking on self-reported fatigue, cognition, neuroendocrine biomarkers and cardiometabolic risk markers in overweight/obese adults. DESIGN: Randomised two-condition crossover trial. SETTING: Laboratory study conducted in Melbourne, Australia. PARTICIPANTS: 19 overweight/obese adults (45-75 years). INTERVENTIONS: After an initial 2 h period seated, participants consumed a meal-replacement beverage and completed (on 2 days separated by a 6-day washout period) each condition over the next 5 h: uninterrupted sitting (sedentary condition) or sitting with 3 min bouts of light-intensity walking every 30 min (active condition). PRIMARY OUTCOME MEASURES: Self-reported fatigue, executive function and episodic memory at 0 h, 4 h and 7 h. SECONDARY OUTCOME MEASURES: Neuroendocrine biomarkers and cardiometabolic risk markers (blood collections at 0 h, 4 h and 7 h, blood pressure and heart rate measured hourly and interstitial glucose measured using a continuous glucose monitoring system). RESULTS: During the active condition, fatigue levels were lower at 4 h (-13.32 (95% CI -23.48 to -3.16)) and at 7 h (-10.73 (95% CI -20.89 to -0.58)) compared to the sedentary condition. Heart rate was higher at 4 h (4.47 (95% CI 8.37 to 0.58)) and at 7 h (4.32 (95% CI 8.21 to 0.42)) during the active condition compared to the sedentary condition. There were no significant differences between conditions by time for other variables. In the sedentary condition, changes in fatigue scores over time correlated with a decrease in heart rate and plasma dihydroxyphenylalanine (DOPA) and an increase in plasma dihydroxyphenylglycol (DHPG). CONCLUSIONS: Interrupting prolonged sitting with light-intensity walking breaks may be an effective fatigue countermeasure acutely. Fatigue levels corresponded with the heart rate and neuroendocrine biomarker changes in uninterrupted sitting in this pilot study. Further research is needed to identify potential implications, particularly for the occupational health context. TRIAL REGISTRATION NUMBER: ACTRN12613000137796; Results.

Associations between five-factor model of the Positive and Negative Syndrome Scale and plasma levels of monoamine metabolite in patients with schizophrenia.

The five-factor model of the Positive and Negative Syndrome Scale (PANSS) for schizophrenia symptoms is the most common multiple-factor model used in analyses; its use may improve evaluation of symptoms in schizophrenia patients. Plasma monoamine metabolite levels are possible indicators of clinical symptoms or response to antipsychotics in schizophrenia. We investigated the association between five-factor model components and plasma monoamine metabolites levels to explore the model's biological basis. Plasma levels of homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were measured using high-performance liquid chromatography in 65 Japanese patients with schizophrenia. Significant negative correlation between plasma 5-HIAA levels and the depression/anxiety component was found. Furthermore, significant positive correlation was found between plasma MHPG levels and the excitement component. Plasma HVA levels were not correlated with any five-factor model component. These results suggest that the five-factor model of the PANSS may have a biological basis, and may be useful for elucidating the psychopathology of schizophrenia. Assessment using the five-factor model may enable understanding of monoaminergic dysfunction, possibly allowing more appropriate medication selection. Further studies of a larger number of first-episode schizophrenia patients are needed to confirm and extend these results.

Pharmacodynamics of norepinephrine reuptake inhibition: Modeling the peripheral and central effects of atomoxetine, duloxetine, and edivoxetine on the biomarker 3,4-dihydroxyphenylglycol in humans.

Norepinephrine, a neurotransmitter in the autonomic sympathetic nervous system, is deaminated by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). Inhibition of the NE transporter (NET) using DHPG as a biomarker was evaluated using atomoxetine, duloxetine, and edivoxetine as probe NET inhibitors. Pharmacokinetic and pharmacodynamic data were obtained from healthy subjects (n = 160) from 5 clinical trials. An indirect response model was used to describe the relationship between drug plasma concentration and DHPG concentration in plasma and cerebrospinal fluid (CSF). The baseline plasma DHPG concentration (1130-1240 ng/mL) and Imax (33%-37%) were similar for the 3 drugs. The unbound plasma drug IC50 (IC50U ) based on plasma DHPG was 0.973 nM for duloxetine, 0.136 nM for atomoxetine, and 0.041 nM for edivoxetine. The baseline CSF DHPG concentration (1850-2260 ng/mL) was similar for the 3 drugs, but unlike plasma DHPG, the Imax for DHPG was 38% for duloxetine, 53% for atomoxetine, and75% for edivoxetine. The IC50U based on CSF DHPG was 2.72 nM for atomoxetine, 1.22 nM for duloxetine, and 0.794 nM for edivoxetine. These modeling results provide insights into the pharmacology of NET inhibitors and the use of DHPG as a biomarker.

Plasma biomarkers of decreased vesicular storage distinguish Parkinson disease with orthostatic hypotension from the parkinsonian form of multiple system atrophy.

BACKGROUND: Parkinson disease with orthostatic hypotension (PD + OH) and the parkinsonian form of multiple system atrophy (MSA-P) can be difficult to distinguish clinically. Recent studies indicate that PD entails a vesicular storage defect in catecholaminergic neurons. Although cardiac sympathetic neuroimaging by (18)F-dopamine positron emission tomography can identify decreased vesicular storage, this testing is not generally available. We assessed whether plasma biomarkers of a vesicular storage defect can separate PD + OH from MSA-P. METHODS: We conceptualized that after F-dopamine injection, augmented production of F-dihydroxyphenylacetic acid (F-DOPAC) indicates decreased vesicular storage, and we therefore predicted that arterial plasma F-DOPAC would be elevated in PD + OH but not in MSA-P. We measured arterial plasma F-DOPAC after (18)F-dopamine administration (infused i.v. over 3 min) in patients with PD + OH (N = 12) or MSA-P (N = 21) and in healthy control subjects (N = 26). Peak F-DOPAC:dihydroxyphenylglycol (DHPG) was also calculated to adjust for effects of denervation on F-DOPAC production. RESULTS: Plasma F-DOPAC accumulated rapidly after initiation of (18)F-dopamine infusion. Peak F-DOPAC (5-10 min) in PD + OH averaged three times that in MSA-P (P < 0.0001). Among MSA-P patients, none had peak F-DOPAC > 300 nCi-kg/cc-mCi, in contrast with 7 of 12 PD + OH patients (χ(2) = 16.6, P < 0.0001). DHPG was lower in PD + OH (3.83 ± 0.36 nmol/L) than in MSA-P (5.20 ± 0.29 nmol/L, P = 0.007). All MSA-P patients had peak F-DOPAC:DHPG < 60, in contrast with 9 of 12 PD + OH patients (χ(2) = 17.5, P < 0.0001). Adjustment of peak F-DOPAC for DHPG increased test sensitivity from 58 to 81% at similar high specificity. INTERPRETATION: After F-dopamine injection, plasma F-DOPAC and F-DOPAC:DHPG distinguish PD + OH from MSA-P.

A pharmacokinetic/pharmacodynamic investigation: assessment of edivoxetine and atomoxetine on systemic and central 3,4-dihydroxyphenylglycol, a biochemical marker for norepinephrine transporter inhibition.

Inhibition of norepinephrine (NE) reuptake into noradrenergic nerves is a common therapeutic target in the central nervous system (CNS). In noradrenergic nerves, NE is oxidized by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). In this study, 40 healthy male subjects received the NE transporter (NET) inhibitor edivoxetine (EDX) or atomoxetine (ATX), or placebo. The pharmacokinetic and pharmacodynamic profile of these drugs in plasma and cerebrospinal fluid (CSF) was assessed. In Part A, subjects received EDX once daily (QD) for 14 or 15 days at targeted doses of 6mg or 9mg. In Part B, subjects received 80mg ATX QD for 14 or 15 days. Each subject received a lumbar puncture before receiving drug and after 14 or 15 days of dosing. Plasma and urine were collected at baseline and after 14 days of dosing. Edivoxetine plasma and CSF concentrations increased dose dependently. The time to maximum plasma concentration of EDX was 2h, and the half-life was 9h. At the highest EDX dose of 9mg, DHPG concentrations were reduced from baseline by 51% at 8h postdose in CSF, and steady-state plasma and urine DHPG concentrations decreased by 38% and 26%, respectively. For 80mg ATX, the decrease of plasma, CSF, or urine DHPG was similar to EDX. Herein we provide clinical evidence that EDX and ATX decrease DHPG concentrations in the periphery and CNS, presumably via NET inhibition. EDX and ATX concentrations measured in the CSF confirmed the availability of those drugs in the CNS.