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ImportanceLess than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant.ObjectiveTo determine the relative effectiveness and safety of 3 common alternate treatments for MDD.Design, setting, and participantsFrom December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks.InterventionsSwitch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase).Main outcomes and measuresThe primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects.ResultsAmong 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain.Conclusions and relevanceAmong a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach.Trial registrationclinicaltrials.gov Identifier: NCT01421342.

Background: Major depressive disorder (MDD) contributes to suicide risk. Treating MDD effectively is considered a key suicide prevention intervention. Yet many patients with MDD do not respond to their initial medication and require a 'next-step'. The relationship between next-step treatments and suicidal thoughts and behaviors is uncharted. Method: The VA Augmentation and Switching Treatments for Depression trial randomized 1522 participants to one of three next-step treatments: Switching to Bupropion, combining with Bupropion, and augmenting with Aripiprazole. In this secondary analysis, features associated with lifetime suicidal ideation (SI) and attempts (SA) at baseline and current SI during treatment were explored. Results: Compared to those with SI only, those with lifetime SI + SA were more likely to be female, divorced, or separated, unemployed; and to have experienced more childhood adversity. They had a more severe depressive episode and were more likely to respond to 'next-step' treatment. The prevalence of SI decreased from 46.5% (694/1492) at baseline to 21.1% (315/1492) at end-of-treatment. SI during treatment was associated with baseline SI; low positive mental health, more anxiety, greater severity and longer duration of current MDD episode; being male and White; and treatment with S-BUP or C-BUP as compared to A-ARI. Conclusion: SI declines for most patients during next-step medication treatments. But about 1 in 5 experienced emergent or worsening SI during treatment, so vigilance for suicide risk through the entire 12-week acute treatment period is necessary. Treatment selection may affect the risk of SI. [ABSTRACT FROM AUTHOR]

PF‐05212377 (SAM760) is a potent and selective 5‐HT6 antagonist, previously under development for the treatment of Alzheimer's disease. In vitro, PF‐05212377 was determined to be a P‐gp/non‐BCRP human transporter substrate. Species differences were observed in the in vivo brain penetration of PF‐05212377 with a ratio of the unbound concentration in brain/unbound concentration in plasma (Cbu/Cpu) of 0.05 in rat and 0.64 in non‐human primates (NHP). Based on pre‐clinical evidence, brain penetration and target engagement of PF‐05212377 was confirmed in NHP using positron emission tomography (PET) measured 5‐HT6 receptor occupancy (%RO). The NHP Cpu EC50 of PF‐05212377 was 0.31 nM (consistent with the in vitro human 5HT6 Ki: 0.32 nM). P‐gp has been reported to be expressed in higher abundance at the rat BBB and in similar abundance at the BBB of non‐human primates and human; brain penetration of PF‐05212377 in humans was postulated to be similar to that in non‐human primates. In humans, PF‐05212377 demonstrated dose and concentration dependent increases in 5‐HT6 RO; maximal 5‐HT6 RO of ∼80% was measured in humans at doses of ≥15 mg with an estimated unbound plasma EC50 of 0.37 nM (which was similar to the in vitro human 5HT6 binding Ki 0.32 nM). In conclusion, cumulative evidence from NHP and human PET RO assessments confirmed that NHP is more appropriate than the rat for the prediction of human brain penetration of PF‐05212377, a P‐gp/non‐BCRP substrate. Clinical trial number: NCT01258751. [ABSTRACT FROM AUTHOR]

Serotonergic neurotransmission plays a key role in the pathophysiology and treatment of various neuropsychiatric diseases. The purpose of this study was to investigate changes in serotonergic neurotransmission after acute tryptophan depletion (ATD) using positron emission tomography (PET) with [11C]P943, a 5‐HT1B receptor radioligand previously shown to be sensitive to changes in 5‐HT. Five healthy subjects were scanned on a high resolution PET scanner twice on the same day, before and approximately 5 hours after ingesting capsules containing an amino acid mixture that lacks tryptophan. For each scan, emission data were acquired for 120 min after intravenous bolus injection of [11C]P943. Binding potential (BPND) values were estimated from parametric images using the second version of the multilinear reference tissue model (MRTM2, t* = 20 min) with cerebellar grey matter used as a reference region. The change in [11C]P943 binding (ΔBPND, %) was calculated as (BPND,post − BPND,pre)/(BPND,pre) × 100, and correlation analysis was performed to measure linear associations of ΔBPND between raphe and other regions of interest (ROIs). ΔBPND ranged from −6% to 45% in the raphe, with positive values indicating reduced competition from 5‐HT. In cortical regions, ΔBPND ranged from −28% to 7%. While these changes did not reach significance, there were significant negative correlations of ΔBPND of the raphe with those of cerebral cortical regions and the thalamus (e.g., r = −.96, p =.011 for average cortex). These findings support the hypothesis that raphe serotonin is a critical modulator of cortical serotonin release via projecting neurons in healthy human subjects. [ABSTRACT FROM AUTHOR]

Positron emission tomography tracers [11C]ABP688 and [18F]FPEB target the metabotropic glutamate receptor subtype 5 providing quantification of the brain glutamatergic system in vivo. Previous [11C]ABP688 positron emission tomography human test–retest studies indicate that, when performed on the same day, significant binding increases are observed; however, little deviation is reported when scans are >7 days apart. Due to the small cohorts examined previously (eight and five males, respectively), we aimed to replicate the same-day test–retest studies in a larger cohort including both males and females. Results confirmed large within-subject binding differences (ranging from −23% to 108%), suggesting that measurements are greatly affected by study design. We further investigated whether this phenomenon was specific to [11C]ABP688. Using [18F]FPEB and methodology that accounts for residual radioactivity from the test scan, four subjects were scanned twice on the same day. In these subjects, binding estimates increased between 5% and 39% between scans. Consistent with [11C]ABP688, mean absolute test–retest variability was previously reported as <12% when scans were >21 days apart. This replication study and pilot extension to [18F]FPEB suggest that observed within-day binding variation may be due to characteristics of mGluR5; for example, diurnal variation in mGluR5 may affect measurement of this receptor. [ABSTRACT FROM AUTHOR]

Measurements of drug occupancies using positron emission tomography (PET) can be biased if the radioligand concentration exceeds “tracer” levels. Negative bias would also arise in successive PET scans if clearance of the radioligand is slow, resulting in a carryover effect. We developed a method to (1) estimate the in vivo dissociation constant Kd of a radioligand from PET studies displaying a non-tracer carryover (NTCO) effect and (2) correct the NTCO bias in occupancy studies taking into account the plasma concentration of the radioligand and its in vivo Kd. This method was applied in a study of healthy human subjects with the histamine H3 receptor radioligand [11C]GSK189254 to measure the PK-occupancy relationship of the H3 antagonist PF-03654746. From three test/retest studies, [11C]GSK189254 Kd was estimated to be 9.5 ± 5.9 pM. Oral administration of 0.1 to 4 mg of PF-03654746 resulted in occupancy estimates of 71%–97% and 30%–93% at 3 and 24 h post-drug, respectively. NTCO correction adjusted the occupancy estimates by 0%–15%. Analysis of the relationship between corrected occupancies and PF-03654746 plasma levels indicated that PF-03654746 can fully occupy H3 binding sites (ROmax = 100%), and its IC50 was estimated to be 0.144 ± 0.010 ng/mL. The uncorrected IC50 was 26% higher. [ABSTRACT FROM AUTHOR]

Purpose: [F]FPEB is a promising PET radioligand for the metabotropic glutamate receptor 5 (mGluR5), a potential target for the treatment of neuropsychiatric diseases. The purpose of this study was to evaluate the test-retest reproducibility of [F]FPEB in the human brain. Methods: Seven healthy male subjects were scanned twice, 3 - 11 weeks apart. Dynamic data were acquired using bolus plus infusion of 162 ± 32 MBq [F]FPEB. Four methods were used to estimate volume of distribution ( V): equilibrium analysis (EQ) using arterial (EQ) or venous input data (EQ), MA1, and a two-tissue compartment model (2 T). Binding potential ( BP) was also estimated using cerebellar white matter (CWM) or gray matter (CGM) as the reference region using EQ, 2 T and MA1. Absolute test-retest variability (aTRV) of V and BP were calculated for each method. Venous blood measurements ( C) were compared with arterial input ( C) to examine their usability in EQ analysis. Results: Regional V estimated by the four methods displayed a high degree of agreement ( r ranging from 0.83 to 0.99 among the methods), although EQ and EQ overestimated V by a mean of 9 % and 7 %, respectively, compared to 2 T. Mean values of aTRV of V were 11 % by EQ, 12 % by EQ, 14 % by MA1 and 14 % by 2 T. Regional BP also agreed well among the methods and mean aTRV of BP was 8 - 12 % (CWM) and 7 - 9 % (CGM). Venous and arterial blood concentrations of [F]FPEB were well matched during equilibrium ( C = 1.01 · C, r = 0.95). Conclusion: [F]FPEB binding shows good TRV with minor differences among analysis methods. Venous blood can be used as an alternative for input function measurement instead of arterial blood in EQ analysis. Thus, [F]FPEB is an excellent PET imaging tracer for mGluR5 in humans. [ABSTRACT FROM AUTHOR]

Purpose: Activated microglia play a key role in inflammatory demyelinating injury in multiple sclerosis (MS). Microglial activation can be measured in vivo using a positron emission tomography (PET) ligand C-PBR28. We evaluated the test-retest variability (TRV) and lesion detectability of C-PBR28 binding in MS subjects and healthy controls (HCs) with high-resolution PET. Methods: Four clinically and radiologically stable relapsing-remitting MS subjects (age 41 ± 7 years, two men/two women) and four HCs (age 42 ± 8 years, 2 two men/two women), matched for translocator protein genotype [two high- and two medium-affinity binders according to DNA polymorphism (rs6971) in each group], were studied for TRV. Another MS subject (age 41 years, male) with clinical and radiological activity was studied for lesion detectability. Dynamic data were acquired over 120 min after injection of 634 ± 101 MBq C-PBR28. For the TRV study, subjects were scanned twice, on average 1.4 weeks apart. Volume of distribution ( V) derived from multilinear analysis (MA1) modeling ( t* = 30 min, using arterial input data) was the main outcome measure. Results: Mean test V values (ml cm) were 3.9 ± 1.4 in the whole brain gray matter (GM), 3.6 ± 1.2 in the whole brain white matter (WM) or normal-appearing white matter (NAWM), and 3.3 ± 0.6 in MS WM lesions; mean retest V values were 3.7 ± 1.0 in GM, 3.3 ± 0.9 in WM/NAWM, and 3.3 ± 0.7 in MS lesions. Test-retest results showed a mean absolute TRV ranging from 7 to 9 % across GM, WM/NAWM, and MS lesions. High-affinity binders demonstrated 30 % higher V than medium-affinity binders in GM. Focal C-PBR28 uptake was detected in two enhancing lesions of the active MS patient. Conclusion: High-resolution C-PBR28 PET can visualize focal areas where microglial activation is known to be present and has good test-retest reproducibility in the human brain. C-PBR28 PET is likely to be valuable for monitoring both MS disease evolution and response to therapeutic strategies that target microglial activation. [ABSTRACT FROM AUTHOR]

Purpose: [C]P943 is a novel, highly selective 5-HT PET radioligand. The aim of this study was to determine the test-retest reliability of [C]P943 using two different modeling methods and to perform a power analysis with each quantification technique. Methods: Seven healthy volunteers underwent two PET scans on the same day. Regions of interest (ROIs) were the amygdala, hippocampus, pallidum, putamen, insula, frontal, anterior cingulate, parietal, temporal and occipital cortices, and cerebellum. Two multilinear radioligand quantification techniques were used to estimate binding potential: MA1, using arterial input function data, and the second version of the multilinear reference tissue model analysis (MRTM2), using the cerebellum as the reference region. Between-scan percent variability and intraclass correlation coefficients (ICC) were used to assess test-retest reliability. We also performed power analyses to determine the method that would allow the least number of subjects using within-subject or between-subject study designs. A voxel-wise ICC analysis for MRTM2 BP was performed for the whole brain and all the ROIs studied. Results: Mean percent variability between two scans across regions ranged between 0.4 % and 12.4 % for MA1 BP, 0.5 % and 11.5 % for MA1 BP, 16.7 % and 28.3 % for MA1 BP, and between 0.2 % and 5.4 % for MRTM2 BP. The power analyses showed a greater number of subjects were required using MA1 BP compared with other outcome measures for both within-subject and between-subject study designs. ICC values were the highest using MRTM2 BP and the lowest with MA1 BP in ten ROIs. Small regions and regions with low binding had lower ICC values than large regions and regions with high binding. Conclusion: Reliable measures of 5-HT receptor binding can be obtained using the novel PET radioligand [C]P943. Quantification of 5-HT receptor binding with MRTM2 BP and with MA1 BP provided the least variability and optimal power for within-subject and between-subject designs. [ABSTRACT FROM AUTHOR]

[11C]AFM, or [11C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine, is a new positron emission tomography (PET) radioligand with high affinity and selectivity for the serotonin transporter (SERT). The purpose of this study was to determine the most appropriate kinetic model to quantify [11C]AFM binding in the healthy human brain. Positron emission tomography data and arterial input functions were acquired from 10 subjects. Compartmental modeling and the multilinear analysis-1(MA1) method were tested using the arterial input functions. The one-tissue model showed a lack of fit in low-binding regions, and the two-tissue model failed to estimate parameters reliably. Regional time-activity curves were well described by MA1. The rank order of [11C]AFM binding potential (BPND) matched well with the known regional SERT densities. For routine use of [11C]AFM, several noninvasive methods for quantification of regional binding were evaluated, including simplified reference tissue models (SRTM and SRTM2), and multilinear reference tissue models (MRTM and MRTM2). The best methods for region of interest (ROI) analysis were MA1, MRTM2, and SRTM2, with fixed population kinetic values ( or b′) for the reference methods. The MA1 and MRTM2 methods were best for parametric imaging. These results showed that [11C]AFM is a suitable PET radioligand to image and quantify SERT in humans. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Noradrenergic dysfunction is implicated in obesity. The norepinephrine transporter (NET) regulates the synaptic availability of norepinephrine. However, NET availability has not been previously characterized in vivo in obese people using Positron Emission Tomography (PET) imaging. Here we report findings evaluating NET availability in individuals with obesity and matched lean (i.e., normal weight) comparison subjects. Methods: Seventeen obese but otherwise healthy individuals with a mean±SD body mass index (BMI) of 34.7±2.6 and 17 lean individuals with a mean±SD BMI of 23.1±1.4 were studied using a high-resolution research tomograph (HRRT) and (S,S)-[11C]O-methylreboxetine ([11C]-MRB), a radioligand selective for the NET. The regional brain NET binding potential (BP ND) was estimated by the multilinear reference tissue model 2 (MRTM2) with the occipital cortex as a reference region. BP ND for regions of interest were obtained with the Automated Anatomic Labeling (AAL) template registered to individual's structural MR scans. Results: Obese individuals had lower NET BP ND values in the thalamus (p <0.038, 27% reduction) including within the pulvinar (p <0.083, 30% reduction), but not in the hypothalamus, locus coeruleus or the raphe nuclei, compared to lean individuals. When age was included as a covariate, the difference in NET BP ND values remained significant in the thalamus (p <0.025) and pulvinar (p <0.042). Conclusions: These results indicate that NET availability is decreased in the thalamus, including the pulvinar, in obese individuals. These findings further support data indicating noradrenergic dysfunction in obesity and suggest impaired NE clearance in obesity. [Copyright &y& Elsevier]