Serotonin receptors (5-HTRs) are implicated in the pathophysiology of a variety of neuropsychiatric and neurodegenerative disorders and are also targets for drug therapy. In the CNS, most of these receptors are expressed in high abundance in specific brain regions reflecting their role in brain functions. Quantifying binding to 5-HTRs in vivo may permit assessment of physiologic and pathologic conditions, and monitoring disease progression, evaluating treatment response, and for investigating new treatment modalities. Positron emission tomography (PET) molecular imaging has the sensitivity to quantify binding of 5-HTRs in CNS disorders and to measure drug occupancy as part of a process of new drug development. Although research on PET imaging of 5-HTRs have been performed more than two decades, the successful radiotracers so far developed for human studies are limited to 5-HT1AR, 5-HT1BR, 5-HT2AR, 5-HT4R and 5-HT6R. Herein we review the development and application of radioligands for PET imaging of 5-HTRs in living brain.
Molecular imaging; PET; 5-HTR; radioligands
Identifying the depression symptoms most closely associated with suicidal thoughts and which medications provide the fastest relief may help suicide prevention.
Post hoc analysis of data from a randomized, double-blind, eight-week clinical trial of the serotonin reuptake inhibitor paroxetine (N=36) versus the norepinephrine-dopamine reuptake inhibitor bupropion (N=38) in patients with DSM-IV major depressive disorder and past suicide attempt or current suicidal thoughts. Treatment effects on Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory symptom clusters were compared. We hypothesized a superior effect of paroxetine on non-suicide, affective/cognitive depression symptom clusters that our prior work found to be associated with suicidal thoughts and attempts. Data were collected from February 2005 to January 2010.
There was a treatment main effect on HDRS Psychic Depression (depressed mood, guilt, retardation, helpless, hopeless, worthless) (estimate = −2.2, 95% CI = −3.2 to −1.1, t = −4.01, df = 67.16, p < 0.001), one of the clusters most strongly correlated to suicidal ideation. The net drug effect was 2.2 points lower average Psychic Depression scores after one week of paroxetine, compared to bupropion, and was statistically significant until Week 4. Results for other depression scale factors were non-significant (p > 0.05).
The results require replication, but suggest a pathway by which SSRI treatment may exert a stronger effect compared with NDRI treatment on reduction of suicidal thoughts during initial weeks of pharmacotherapy in these higher risk patients.
Suicide; depression; symptom cluster; antidepressant; clinical trial
To investigate relationships of depressed parents' attachment style to offspring suicidal behavior.
244 parents diagnosed with a DSM-IV depressive episode completed the Adult Attachment Questionnaire at study entry. Baseline and yearly follow-up interviews of their 488 offspring tracked suicidal behavior and psychopathology. Survival analysis and marginal regression models with correlated errors for siblings investigated the relationship between parent insecure attachment traits and offspring characteristics. Data analyzed were collected 1992–2008 during a longitudinal family study completed January 31, 2014.
Parent avoidant attachment predicted offspring suicide attempts at a trend level (p=0.083). Parent anxious attachment did not predict offspring attempts (p=0.961). In secondary analyses, anxious attachment in parents was associated with offspring impulsivity (p=0.034), and in offspring suicide attempters, was associated with greater intent (p=0.045) and lethality of attempts (p=0.003). Avoidant attachment in parents was associated with offspring impulsivity (p=0.025) and major depressive disorder (p=0.012). Parent avoidant attachment predicted a greater number of suicide attempts (p=0.048) and greater intent in offspring attempters (p=0.003). Results were comparable after adjusting for parent diagnosis of borderline personality disorder.
Insecure avoidant, but not anxious, attachment in depressed parents may predict offspring suicide attempt. Insecure parent attachment traits were associated with impulsivity and major depressive disorder in all offspring, and with more severe suicidal behavior in offspring attempters. Insecure parental attachment merits further study as a potential target to reduce risk of offspring psychopathology and more severe suicidal behavior.
Attachment; Suicide attempt; Family study; Impulsivity; Depression
Pharmacologic blockade of monoamine oxidase A (MAOA) or serotonin transporter (5-HTT) has antidepressant and anxiolytic efficacy in adulthood. Yet, genetically conferred MAOA or 5-HTT hypo-activity is associated with altered aggression and increased anxiety/depression. Here we test the hypothesis that increased monoamine signaling during development causes these paradoxical aggressive and affective phenotypes. We find that pharmacologic MAOA blockade during early postnatal development (P2-P21) but not during peri-adolescence (P22-41) increases anxiety- and depression-like behavior in adult (> P90) mice, mimicking the effect of P2-21 5-HTT inhibition. Moreover, MAOA blockade during peri-adolescence, but not P2-21 or P182-201, increases adult aggressive behavior, and 5-HTT blockade from P22-P41 reduced adult aggression. Blockade of the dopamine transporter, but not the norepinephrine transporter, during P22-41 also increases adult aggressive behavior. Thus, P2-21 is a sensitive period during which 5-HT modulates adult anxiety/depression-like behavior, and P22-41 is a sensitive period during which DA and 5-HT bi-directionally modulate adult aggression. Permanently altered DAergic function as a consequence of increased P22-P41 monoamine signaling might underlie altered aggression. In support of this hypothesis, we find altered aggression correlating positively with locomotor response to amphetamine challenge in adulthood. Proving that altered DA function and aggression are causally linked, we demonstrate that optogenetic activation of VTA DAergic neurons increases aggression. It therefore appears that genetic and pharmacologic factors impacting dopamine and serotonin signaling during sensitive developmental periods can modulate adult monoaminergic function and thereby alter risk for aggressive and emotional dysfunction.
Serotonin; Dopamine; Development; Aggression; Anxiety; Depression; Mouse
To compare structured clinical assessment versus research measurement of suicidal risk among inpatients with major depression.
50 depressed inpatients underwent a structured clinical and an independent research assessment of suicidal risk. Agreement between both assessments and its impact upon time to first readmission was tested.
A false negative rate of 25% in the clinical screening of past suicide attempts was associated with older age, concealment and reported lower frequency of suicidal thoughts. Mean times to first readmission (2.5-years follow-up) were 74 weeks (discordant responders) and 118 weeks (concordant responders).
A failure to detect 25% of patients with past suicide attempt history in the clinical assessment was associated with older age and concealment of suicidal thoughts.
Suicide, Attempted; Depression; Inpatients; Diagnostic Errors; Assessment, Risk; Bipolar Disorder
Heschl’s gyrus (HG) is reported to have a normal left>right hemispheric volume asymmetry, and reduced asymmetry in schizophrenia. Primary auditory cortex (A1) occupies the caudal-medial surface of HG, but it is unclear if A1 has normal asymmetry, or whether its asymmetry is altered in schizophrenia. To address these issues, we compared bilateral gray matter volumes of HG and A1, and neuron density and number in A1, in autopsy brains from male subjects with or without schizophrenia. Comparison of diagnostic groups did not reveal altered gray matter volumes, neuron density, neuron number or hemispheric asymmetries in schizophrenia. With respect to hemispheric differences, HG displayed a clear left>right asymmetry of gray matter volume. Area A1 occupied nearly half of HG, but had less consistent volume asymmetry, that was clearly present only in a subgroup of archival brains from elderly subjects. Neuron counts, in layers IIIb-c and V-VI, showed that the A1 volume asymmetry reflected differences in neuron number, and was not caused simply by changes in neuron density. Our findings confirm previous reports of striking hemispheric asymmetry of HG, and additionally show evidence that A1 has a corresponding asymmetry, although less consistent than that of HG.
cerebral cortex; human; postmortem; stereology; neuron number
Clinically useful predictors of treatment outcome in major depressive disorder (MDD) remain elusive. We examined associations between functional magnetic resonance imaging (fMRI) blood oxygen level dependent (BOLD) signal during active negative word processing and subsequent selective serotonin reuptake inhibitor (SSRI) treatment outcome in MDD. Unmedicated MDD subjects (n=17) performed an emotional word processing fMRI task, and then received eight weeks of standardized antidepressant treatment with escitalopram. Lower pre-treatment BOLD responses to negative words in midbrain, dorsolateral prefrontal cortex, paracingulate, anterior cingulate, thalamus and caudate nuclei correlated significantly with greater improvement following escitalopram treatment. Activation of these regions in response to negative words correlated significantly with reaction time for rating word relevance. Maximally predictive clusters of voxels identified using a cross-validation approach predicted 48% of the variance in response to treatment. This study provides preliminary evidence that SSRIs may be most beneficial in patients who are less able to engage cognitive control networks while processing negative stimuli. Differences between these findings and previous fMRI studies of SSRI treatment outcome may relate to differences in task design. Regional BOLD responses to negative words predictive of SSRI outcome in this study were both overlapping and distinct from those predictive of outcome with cognitive behavioral therapy (CBT) in previous studies using the same task. Future studies may examine prediction of differential outcome across treatments in the context of a randomized controlled trial.
fMRI; major depressive disorder; biomarker; SSRI; prediction; treatment outcome
In 2009 FDA issued a black box warning for varenicline and neuropsychiatric events. We studied efficacy (smoking cessation) of varenicline, and safety (neuropsychiatric events) in both randomized clinical trials (RCTs) and a large observational study. The observational study was included to determine the generalizability of the RCT findings to the general population.
RCTs: Re-analysis of all 17 placebo controlled RCTs (n=8027) of varenicline conducted by Pfizer using complete intent-to-treat person-level longitudinal data.
Analysis of Department of Defense collected adverse neuropsychiatric adverse event data in inpatients and outpatients taking varenicline versus nicotine replacement therapy (NRT) (n=35,800). The primary endpoints for the RCTs were smoking abstinence and adverse event reports of suicidal thoughts and behavior, depression, aggression/agitation, and nausea. The effect of varenicline in patients with (n=1004) and without (n=7023) psychiatric disorders was examined. The primary endpoints for the observational study were anxiety, depression, drug induced mental disorder, episodic and mood disorder, other psychiatric disorder, post traumatic stress disorder, schizophrenia, suicide attempt, transient mental disorder.
RCTs: Varenicline did not increase rates of suicidal events, depression, or aggression/agitation. Varenicline increased risk of nausea (OR=3.69, 95% CI = (3.03, 4.48), p<0.0001). Varenicline increased rate of abstinence by 124% compared to placebo (p<0.0001), and 22% compared to bupropion (p<0.0001). While having a current psychiatric disorder or history of psychiatric illness increased the risk of neuropsychiatric events, it did so equally in treated and control patients.
Following propensity score matching, overall rate of neuropsychiatric disorders was lower for varenicline versus NRT (2.28% versus 3.16%, p<0.0001).
In the RCTs, varenicline revealed no increased risk of neuropsychiatric adverse events relative to placebo. Varenicline provided greater benefit in terms of smoking cessation relative to both placebo and bupropion. The same results were observed in patients with and without a current psychiatric disorder or history of psychiatric illness. In the observational study, the overall rate of neuropsychiatric disorders was lower in patients treated with varenicline relative to NRT, revealing that the finding of no increased risk of neuropsychiatric adverse events in RCTs generalizes to the population of patients engaging in treatment with varenicline.
Many species use tools, but the mechanisms underpinning the behaviour differ between species and even among individuals within species, depending on the variants performed. When considering tool use ‘as adaptation’, an important first step is to understand the contribution made by fixed phenotypes as compared to flexible mechanisms, for instance learning. Social learning of tool use is sometimes inferred based on variation between populations of the same species but this approach is questionable. Specifically, alternative explanations cannot be ruled out because population differences are also driven by genetic and/or environmental factors. To better understand the mechanisms underlying routine but non-universal (i.e. habitual) tool use, we suggest focusing on the ontogeny of tool use and individual variation within populations. For example, if tool-using competence emerges late during ontogeny and improves with practice or varies with exposure to social cues, then a role for learning can be inferred. Experimental studies help identify the cognitive and developmental mechanisms used when tools are used to solve problems. The mechanisms underlying the route to tool-use acquisition have important consequences for our understanding of the accumulation in technological skill complexity over the life course of an individual, across generations and over evolutionary time.
habitual tool use; ontogeny; social learning; cognition; inhibition; phenotypic plasticity
We previously reported higher serotonin 1A receptor (5-HT1A) binding in subjects with major depressive disorder (MDD) during a major depressive episode using positron emission tomography imaging with [11C]WAY-100635. 5-HT1A receptor binding is also associated with treatment outcome after nonstandardized antidepressant treatment. We examined whether pretreatment 5-HT1A binding is associated with treatment outcome following standardized escitalopram treatment in MDD. We also compared 5-HT1A binding between all MDD subjects in this cohort and a sample of healthy control subjects.
Twenty-four MDD subjects in a current major depressive episode and 51 previously studied healthy control subjects underwent positron emission tomography scanning with [11C]WAY-100635, acquiring a metabolite-corrected arterial input function and free-fraction measurement to estimate 5-HT1A binding potential (BPF = Bmax/KD, where Bmax = available receptors and KD = dissociation constant). Major depressive disorder subjects then received 8 weeks of treatment with escitalopram; remission was defined as a posttreatment 24-item Hamilton Depression Rating Scale <10 and ≥50% reduction in Hamilton Depression Rating Scale.
Remitters to escitalopram had 33% higher baseline 5-HT1A binding in the raphe nuclei than nonremitters (p = .047). Across 12 cortical and subcortical regions, 5-HT1A binding did not differ between remitters and nonremitters (p = .86). Serotonin 1A receptor binding was higher in MDD than control subjects across all regions (p = .0003). Remitters did not differ from nonremitters in several relevant clinical measures.
Elevated 5-HT1A binding in raphe nuclei is associated with subsequent remission with the selective serotonin reuptake inhibitor escitalopram; this is consistent with data from a separate cohort receiving naturalistic antidepressant treatment. We confirmed our previous findings of higher 5-HT1A binding in current MDD compared with control subjects.
Antidepressant; depression; PET imaging; prediction; serotonin 1A receptor; treatment outcome
BALB/c is an inbred stress-sensitive mouse strain exhibiting low brain serotonin (5-HT) content and a 5-HT biosynthetic enzyme tryptophan hydroxylase (Tph2) variant reported to have lower catalytic activity compared to other inbred base strains. To evaluate other mechanisms that may explain low 5-HT, we compared BALB/cJ mice and a control inbred strain C57Bl/6J mice, for expression of Tph2 mRNA, TPH2 protein and regional levels of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA). Tph2 mRNA and TPH2 protein in brainstem dorsal raphe nuclei (DRN) was assayed by in situ hybridization and immunocytochemistry respectively. 5-HT and 5-HIAA were determined by high pressure liquid chromatography (HPLC). BALB/cJ mice had 20% less Tph2 mRNA and 28% fewer TPH2 immunolabeled neurons than C57Bl/6J mice (t = -2.59, p = 0.02). The largest difference in Tph2 transcript expression was in rostral DRN (t = 2.731, p = 0.008). 5-HT was 15% lower in the midbrain of BALB/cJ compared to C57Bl/6J mice (p < 0.05). The behavioral differences in BALB/cJ mice relative to the C57Bl/6J strain may be due in part, to fewer 5-HT neurons and lower Tph2 gene expression resulting in less 5-HT neurotransmission. Future studies quantifying expression per neuron are needed to determine whether less expression is explained by fewer neurons or also less expression per neuron, or both.
Tph2; 5-HT; dorsal raphe nucleus; depression; immunocytochemistry
Bipolar Disorder is a major cause of disability and a high risk for suicide. The pathophysiology of the disorder remains largely unknown. Medication choice for bipolar depression patients involves trial and error. Our group reported previously that brain serotonin 1A (5HT1A) receptor binding measured by positron emission tomography (PET) is higher in bipolar depression. We now investigated whether pretreatment 5HT1A levels correlates with antidepressant medication outcome. 41 medication-free DSM-IV diagnosed, bipolar patients in a major depressive episode (MDE) had brain PET scans performed using [11C]WAY-100635 and a metabolite corrected arterial input function. The patients then received naturalistic psychopharmacologic treatment as outpatients and a follow up Hamilton Depression Rating Scale (HDRS) after 3 months of treatment. Patients with 24 item HDRS scores less than 10 were considered to have remitted. A linear mixed effects model was used to compare BPF (binding potential, proportional to the total number of available receptors) in 13 brain regions of interest between remitters and non-remitters. 34 patients completed 3 months of treatment and ratings; 9 had remitted. Remitters and non-remitters did not differ in age, sex or recent medication history with serotonergic medications. Remitters had higher [11C]WAY-100635 BPF across all brain regions compared with non-remitters (p=0.02). Higher pre-treatment brain 5HT1A receptor binding was associated with remission after 3 months of pharmacological treatment in bipolar depression. Prospective treatment studies are warranted to determine whether this test predicts outcome of specific types of treatment.
Bipolar Disorder; PET; [11C]WAY-100635; Antidepressant; Mood stabilizer
Activation of the innate immune system plays a key role in exacerbations of chronic lung disease, yet the potential role of lung fibroblasts in innate immunity and the identity of epithelial danger signals (alarmins) that may contribute to this process are unclear. The objective of the study was to identify lung epithelial derived alarmins released during endoplasmic reticulum stress (ER stress) and oxidative stress and evaluate their potential to induce innate immune responses in lung fibroblasts. We found that treatment of primary human lung fibroblasts (PHLF) with conditioned media from damaged lung epithelial cells significantly upregulated IL-6, IL-8, MCP-1 and GM-CSF expression (p<0.05). This effect was reduced with anti-IL-1α or IL-1Ra but not anti-IL-1β antibody. Co-stimulation with a TLR3 ligand, Poly I:C, significantly accentuated the IL-1α induced inflammatory phenotype in PHLF, and this effect was blocked with IKK2 and TAKi inhibitors. Finally, Il1r1−/− and Il1a−/− mice exhibit reduced BAL neutrophilia and collagen deposition in response to bleomycin treatment. We conclude that IL-1α plays pivotal role in triggering proinflammatory responses in fibroblasts and this process is accentuated in the presence of dsRNA. This mechanism may be important in the repeated cycles of injury and exacerbation in chronic lung disease.
Offspring of depressed parents are at increased risk for psychiatric disorders. Although bipolar disorder (BD) and major depressive disorder (MDD) are both found in the same families, it is not clear whether transmission to offspring of BD or MDD tends to occur from parents with the same mood disorder subtype. The primary hypothesis was that offspring of parents with BD would be at increased risk for BD and other comorbid disorders common to BD such as anxiety and substance use relative to offspring of parents with MDD. Offspring of parents with BD versus those with MDD were also hypothesized to be at greater risk for externalizing disorders, i.e., conduct disorder, attention-deficit hyperactivity disorder, or antisocial personality disorder.
Parents (n = 320) with mood disorders and their offspring (n = 679) were studied. Adult offspring were administered the Structured Clinical Interview for DSM-IV Axis I Disorders to establish the presence of psychopathology. Offspring aged 10 to 18-years-old were assessed with the School Aged Schedule for Affective Disorders and Schizophrenia, Present and Lifetime version, and parents of children under age 10 completed the Child Behavioral Checklist. Data were examined using Cox Proportional Hazard regression.
There was no difference in hazard of mood disorders in the offspring of parents with BD as compared to offspring of parents with MDD. However, a number of other parent and offspring characteristics increased risk for mood, anxiety, externalizing, and substance use disorders in offspring, including self-reported childhood abuse in parent or offspring, offspring impulsive aggression, and age of onset of parental mood disorder.
Mood disorders are highly familial independent of whether the parent’s condition is unipolar or bipolar, and considerable overlap in the familial basis of MDD and BD was found. Although parental characteristics had limited influence on risk of offspring psychopathology, reported childhood adversity, be it in the parent or child, is a harbinger of negative outcomes. These risk factors extend previous findings, and are consistent with diathesis-stress conceptualizations.
bipolar disorder; familial transmission; major depressive disorder
Omega-3 and n-6 fatty acids are biosynthetic precursors to lipid mediators with antinociceptive and pronociceptive properties. We conducted a randomized, single-blinded, parallel-group clinical trial to assess clinical and biochemical effects of targeted alteration in dietary n-3 and n-6 fatty acids for treatment of chronic headaches. After a 4-week preintervention phase, ambulatory patients with chronic daily headache undergoing usual care were randomized to 1 of 2 intensive, food-based 12-week dietary interventions: a high n-3 plus low n-6 (H3-L6) intervention, or a low n-6 (L6) intervention. Clinical outcomes included the Headache Impact Test (HIT-6, primary clinical outcome), Headache Days per month, and Headache Hours per day. Biochemical outcomes included the erythrocyte n-6 in highly unsaturated fatty acids (HUFA) score (primary biochemical outcome) and bioactive n-3 and n-6 derivatives. Fifty-six of 67 patients completed the intervention. Both groups achieved targeted intakes of n-3 and n-6 fatty acids. In intention-to-treat analysis, the H3-L6 intervention produced significantly greater improvement in the HIT-6 score (−7.5 vs −2.1; P < 0.001) and the number of Headache Days per month (−8.8 vs −4.0; P = 0.02), compared to the L6 group. The H3-L6 intervention also produced significantly greater reductions in Headache Hours per day (−4.6 vs −1.2; P = 0.01) and the n-6 in HUFA score (−21.0 vs −4.0%; P < 0.001), and greater increases in antinociceptive n-3 pathway markers 18-hydroxy-eicosapentaenoic acid (+118.4 vs +61.1%; P < 0.001) and 17-hydroxy-docosahexaenoic acid (+170.2 vs +27.2; P < 0.001). A dietary intervention increasing n-3 and reducing n-6 fatty acids reduced headache pain, altered antinociceptive lipid mediators, and improved quality-of-life in this population.
Omega-3; Omega-6; Headache; Migraine; Clinical trial
Estimating the likelihood of future major depressive episodes (MDEs) would assist clinicians in decision-making regarding the optimal length of treatment for MDE. Unfortunately, little data are available to guide clinical practice.
We followed 200 females and 152 males who responded to treatment for a MDE for 2 years to determine risk factors for future MDE. Cox Proportional Hazard Regression modeled time to first relapse into MDE and mixed effect logistic regression modeled monthly depression status.
Females were more likely than males to experience a MDE in any month of the study, and marginally more likely to experience a relapse. By 12 months, 60% of females had relapsed compared to 51% of males (median time to relapse 8 vs 13 months, respectively). Several factors predicted worse outcome for both men and women: reported childhood abuse, earlier age of onset of first MDE, Bipolar Disorder, unemployment, and more years of education. For females, but not males, suicidal ideation predicted MDE relapse and both suicidal ideation and prior suicide attempts were associated with more time in a MDE.
The naturalistic treatment of participants, exclusion of individuals with current comorbid alcohol or substance use disorder, and a follow up period of two years are limitations.
Women are more vulnerable to relapse and spend more time depressed compared to men. Identification of general and sex-specific risk factors for future depression may provide clinicians with useful tools to estimate need for ongoing pharmacotherapy in MDE.
depression; gender; predictors; relapse; risk; sex
The anterior limb of the internal capsule (ALIC) is the major white matter tract providing reciprocal connections between the frontal cortex, striatum and thalamus. Mounting evidence suggests that this tract may be affected in schizophrenia, with brain imaging studies reporting reductions in white matter volume and density, changes in fractional anisotropy and reduced asymmetry. However, the molecular correlates of these deficits are currently unknown. The aim of this study was to identify alterations in protein and metabolite levels in the ALIC in schizophrenia. Samples were obtained post-mortem from individuals with schizophrenia (n=15) and non-psychiatric controls (n=13). Immunoreactivity for the myelin-associated protein myelin basic protein (MBP), and the axonal-associated proteins phosphorylated neurofilament and SNAP-25 was measured by enzyme-linked immunoadsorbant assay (ELISA). Metabolite concentrations were quantified by proton nuclear magnetic resonance (1H NMR) spectroscopy. Levels of myelin- or axonal-associated proteins did not differ between groups. Overall differences in metabolite concentrations were observed between the two groups (MANOVA F=2.685, p=0.036), with post-hoc tests revealing lower lactate (19%) and alanine (24%) levels in the schizophrenia group relative to controls. Observed changes in lactate and alanine levels indicate metabolic abnormalities within the ALIC in schizophrenia.
myelin; axon; metabolite; internal capsule; lactate
[11C]CUMI-101 is the first selective serotonin receptor (5-HT1AR) partial agonist radiotracer for positron emission tomography (PET) tested in vivo in nonhuman primates and humans. We evaluated specific binding of [3H]CUMI-101 by quantitative autoradiography studies in postmortem baboon and human brain sections using the 5- HT1AR antagonist WAY100635 as a displacer. The regional and laminar distributions of [3H]CUMI-101 binding in baboon and human brain sections matched the known distribution of [3H]8-OH-DPAT and [3H]WAY100635. Prazosin did not measurably displace [3H]CUMI-101 binding in baboon or human brain sections, thereby ruling out [3H]CUMI-101 binding to α1-adrenergic receptors. This study demonstrates that [11C]CUMI-101 is a selective 5-HT1AR ligand for in vivo and in vitro studies in baboon and human brain.
5-HT1AR; brain; serotonin agonist; autoradiography
Sprague Dawley rats (10/sex/group) were given a single iv dose of CUMI-101 to determine acute toxicity of CUMI-101 and radiation dosimetry estimations were conducted in baboons with [11C]CUMI-101. Intravenous administration of CUMI-101 did not produce overt biologically or toxicologically significant adverse effects except transient hypoactivity immediately post dose in the mid and high dose groups, which is not considered to be a dose limiting toxic effect. No adverse effects were observed in the low dose group. The no observed adverse effect level (NOAEL) is considered to be 44.05 µg/kg for a single iv dose administration in rats. The maximum tolerated dose (MTD) was estimated to be 881 µg/kg for a single iv dose administration. The Medical Internal Radiation Dose (MIRDOSE) estimates indicate the maximum, permissible single study dosage of [11C]CUMI-101 in human is 52 mCi with testes and urinary bladder as the critical organ for male and female, respectively.
PET; toxicity; dosimetry; radioligand
Although serotonin receptor and cytoarchitectonic alterations are reported in prefrontal cortex (PFC) in suicide and depression, no study has considered binding relative to neuron density. Therefore, we measured neuron density and SERT, 5-HT1A and 5-HT2A binding in matched suicides and controls.
Suicides and normal controls (N=15 matched pairs) were psychiatrically characterized. Neuron density and binding were determined in dorsal (BA9) and ventral (BA47) PFC by stereology and quantitative autoradiography in near-adjacent sections. Binding index was defined as the ratio of receptor binding to neuron density.
Suicides had lower neuron density in the gyrus of both areas. The binding index was lower for the serotonin transporter in BA47 but not in BA9; the 5-HT1A binding index was higher in BA9 but not in BA47, while the 5-HT2A binding index was not different between groups. SERT binding was lower in suicides in BA47 but not BA9, while 5-HT1A binding was higher in BA9 but not BA47. SERT binding negatively correlated with 5-HT1A binding in BA47 in suicides. Neuron density decreased with age. 5-HT1A binding index was higher in females than males.
We found lower neuron density and lower SERT binding index in both PFC regions in suicides. More 5-HT1A binding with less SERT binding and the negative correlation in depressed suicides suggests post-synaptic receptor upregulation, and it is independent of the difference in neuron density. Thus, abnormalities in both cortical neurons and in their serotonergic innervation are present in suicides and future studies need to determine whether cortical changes reflect the trophic effect of altered serotonin innervation.
serotonin; stereology; receptor binding; human; autoradiography
The 5-HT1AR partial agonist PET radiotracer, [11C]CUMI-101, has advantages over an antagonist radiotracer as it binds preferentially to the high affinity state of the receptor and thereby provides more functionally meaningful information. The major drawback of C-11 tracers is the lack of cyclotron facility in many health care centers thereby limiting widespread clinical or research use. We identified the fluoroethyl derivative, 2-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butyl)-4-methyl-1,2,4-triazine-3,5(2H,4H)dione (FECUMI-101) (Ki = 0.1 nM; Emax = 77%; EC50 = 0.65 nM) as a partial agonist 5-HT1AR ligand of the parent ligand CUMI-101. FECUMI-101 is radiolabeled with F-18 by O-fluoroethylation of the corresponding desmethyl analogue (1) with [18F]fluoroethyltosylate in DMSO in the presence of 1.6 equiv. of K2CO3 in 45 ± 5% yield (EOS). PET shows [18F]FECUMI-101 binds specifically to 5-HT1AR enriched brain regions of baboon. The specificity of [18F]FECUMI-101 binding to 5-HT1AR was confirmed by challenge studies with the known 5-HT1AR ligand WAY100,635. These findings indicate that [18F]FECUMI-101 can be a viable agonist ligand for the in vivo quantification of high affinity 5-HT1AR with PET.
PET; FECUMI-101; 5-HT1AR; agonist; brain; radiotracer
Clinical studies find that childhood adversity and stress-ful life events in adulthood increase the risk for major depression and for suicide. The predispositions to either major depression or suicide are thought to depend on genetic risk factors or epigenetic effects. We investigated DNA methylation signatures postmortem in brains of suicides with diagnosis of major depressive disorder. DNA methylation levels were determined at single C-phosphate-G (CpG) resolution sites within ventral prefrontal cortex of 53 suicides and nonpsychiatric controls, aged 16 to 89 years. We found that DNA methylation increases throughout the lifespan. Suicides showed an 8-fold greater number of methylated CpG sites relative to controls (P<2.2x10-16), with greater DNA methylation changes over and above the increased methylation observed in normal aging. This increased DNA methylation may be a significant contributor to the neuropathology and psychopathology underlying the risk of suicide in depression.
aging; depression; DNA methylation; epigenetics; mood disorder; suicide
Several lines of evidence implicate abnormal serotonergic function in suicidal behavior and completed suicide, including low serotonin transporter binding in postmortem studies of completed suicide. We have also reported low in vivo serotonin transporter binding in major depressive disorder (MDD) during a major depressive episode using positron emission tomography with [11C]McN5652. We quantified regional brain serotonin transporter binding in vivo in depressed suicide attempters, depressed non-attempters, and healthy controls using positron emission tomography and a superior radiotracer, [11C]DASB.
51 subjects with DSM-IV current MDD, 15 of whom were past suicide attempters, and 32 healthy controls underwent PET scanning with [11C]DASB to quantify in vivo regional brain serotonin transporter binding. Metabolite-corrected arterial input functions and plasma free-fraction were acquired to improve quantification.
Depressed suicide attempters had lower serotonin transporter binding in midbrain compared with depressed non-attempters (p=0.031) and controls (p=0.0093). There was no difference in serotonin transporter binding comparing all depressed subjects to healthy controls considering six a priori regions of interest simultaneously (p=0.41).
Low midbrain serotonin transporter binding appears to be related to the pathophysiology of suicidal behavior rather than of major depressive disorder. This is consistent with postmortem work showing low midbrain serotonin transporter binding capacity in depressed suicides, and may partially explain discrepant in vivo findings quantifying serotonin transporter in depression. Future studies should investigate midbrain serotonin transporter binding as a predictor of suicidal behavior in MDD, and determine the cause of low binding.
serotonin transporter; depression; suicide; PET; midbrain; [11C]DASB; pathophysiology
The transcription factor FoxO1 regulates multiple physiological processes. Here, we show that FoxO1 is highly expressed in neurons of the locus coeruleus and of various sympathetic ganglions, but not in the adrenal medulla. Consistent with this pattern of expression, mice lacking FoxO1 only in sympathetic neurons (FoxO1Dbh−/−) display a low sympathetic tone without modification of the catecholamine content in the adrenal medulla. As a result, FoxO1Dbh−/− mice demonstrate an increased insulin secretion, improved glucose tolerance, low energy expenditure, and high bone mass. FoxO1 favors catecholamine synthesis because it is a potent regulator of the expression of Dbh that encodes the initial and rate-limiting enzyme in the synthesis of these neurotransmitters. By identifying FoxO1 as a transcriptional regulator of the sympathetic tone, these results advance our understanding of the control of some aspects of metabolism and of bone mass accrual.
FoxO1; Locus coeruleus; Sympathetic tone