Ventromedial prefrontal cortex/anterior cingulate cortex Glx, glutamate, and GABA levels in medication-free major depressive disorder.

Glutamate (Glu) and gamma-aminobutyric acid (GABA) are implicated in the pathophysiology of major depressive disorder (MDD). GABA levels or GABAergic interneuron numbers are generally low in MDD, potentially disinhibiting Glu release. It is unclear whether Glu release or turnover is increased in depression. Conversely, a meta-analysis of prefrontal proton magnetic resonance spectroscopy (1H MRS) studies in MDD finds low Glx (combination of glutamate and glutamine) in medicated MDD. We hypothesize that elevated Glx or Glu may be a marker of more severe, untreated MDD. We examined ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC) Glx and glutamate levels using 1H MRS in 34 medication-free, symptomatic, chronically ill MDD patients and 32 healthy volunteers, and GABA levels in a subsample. Elevated Glx and Glu were observed in MDD compared with healthy volunteers, with the highest levels seen in males with MDD. vmPFC/ACC GABA was low in MDD. Higher Glx levels correlated with more severe depression and lower GABA. MDD severity and diagnosis were both linked to higher Glx in vmPFC/ACC. Low GABA in a subset of these patients is consistent with our hypothesized model of low GABA leading to glutamate disinhibition in MDD. This finding and model are consistent with our previously reported findings that the NMDAR-antagonist antidepressant effect is proportional to the reduction of vmPFC/ACC Glx or Glu levels.

Large-scale network dynamics in neural response to emotionally negative stimuli linked to serotonin 1A binding in major depressive disorder.

Serotonergic dysfunction is implicated in major depressive disorder (MDD), but the mechanisms of this relationship remain elusive. Serotonin 1A (5-HT1A) autoreceptors regulate brain-wide serotonin neuron firing and are positioned to assert large-scale effects on negative emotion. Here we investigated the relationship between raphe 5-HT1A binding and brain-wide network dynamics of negative emotion. 22 healthy-volunteers (HV) and 27 medication-free participants with MDD underwent positron emission tomography (PET) using [11C]CUMI-101 (CUMI) to quantify 5-HT1A binding in midbrain raphe nuclei and functional magnetic resonance imaging (fMRI) scanning during emotionally negative picture viewing. Causal connectivity across regions responsive to negative emotion was estimated in the fMRI data using a multivariate dynamical systems model. During negative picture viewing, MDD subjects demonstrated significant hippocampal inhibition of amygdala, basal-ganglia, thalamus, orbital frontal cortex, inferior frontal gyrus and dorsomedial prefrontal cortex (IFG, dmPFC). MDD-related connectivity was not associated with raphe 5-HT1A binding. However, greater hippocampal inhibition of amygdala, thalamus, IFG and dmPFC correlated with hippocampal 5-HT1A binding. Correlation between hippocampal 5-HT1A binding and the hippocampal inhibition network was specific to MDD but not HV. MDD and HV groups also differed with respect to the correlation between raphe and hippocampal 5-HT1A binding which was more pronounced in HV. These findings suggest that increased hippocampal network inhibition in MDD is linked to hippocampal serotonergic dysfunction which may in turn arise from disrupted linkage in raphe to hippocampus serotonergic circuitry.

Depression-related anterior cingulate prefrontal resting state connectivity normalizes following cognitive behavioral therapy.

BACKGROUND: Aberrant activity of the subcallosal cingulate (SCC) is a common theme across pharmacologic treatment efficacy prediction studies. The functioning of the SCC in psychotherapeutic interventions is relatively understudied, as are functional differences among SCC subdivisions. We conducted functional connectivity analyses (rsFC) on resting-state functional magnetic resonance imaging (fMRI) data, collected before and after a course of cognitive behavioral therapy (CBT) in patients with major depressive disorder (MDD), using seeds from three SCC subdivisions. METHODS: Resting-state data were collected from unmedicated patients with current MDD (Hamilton Depression Rating Scale-17 > 16) before and after 14-sessions of CBT monotherapy. Treatment outcome was assessed using the Beck Depression Inventory (BDI). Rostral anterior cingulate (rACC), anterior subcallosal cingulate (aSCC), and Brodmann's area 25 (BA25) masks were used as seeds in connectivity analyses that assessed baseline rsFC and symptom severity, changes in connectivity related to symptom improvement after CBT, and prediction of treatment outcomes using whole-brain baseline connectivity. RESULTS: Pretreatment BDI negatively correlated with pretreatment rACC ~ dorsolateral prefrontal cortex and aSCC ~ lateral prefrontal cortex rsFC. In a region-of-interest longitudinal analysis, rsFC between these regions increased post-treatment (p < 0.05FDR). In whole-brain analyses, BA25 ~ paracentral lobule and rACC ~ paracentral lobule connectivities decreased post-treatment. Whole-brain baseline rsFC with SCC did not predict clinical improvement. CONCLUSIONS: rsFC features of rACC and aSCC, but not BA25, correlated inversely with baseline depression severity, and increased following CBT. Subdivisions of SCC involved in top-down emotion regulation may be more involved in cognitive interventions, while BA25 may be more informative for interventions targeting bottom-up processing. Results emphasize the importance of subdividing the SCC in connectivity analyses.

In vivo comparison of N-11CH3 vs O-11CH3 radiolabeled microtubule targeted PET ligands.

Altered dynamics of microtubules (MT) are implicated in the pathophysiology of a number of brain diseases. Therefore, radiolabeled MT targeted ligands that can penetrate the blood brain barrier (BBB) may offer a direct and sensitive approach for diagnosis, and assessing the clinical potential of MT targeted therapeutics using PET imaging. We recently reported two BBB penetrating radioligands, [11C]MPC-6827 and [11C]HD-800 as specific PET ligands for imaging MTs in brain. The major metabolic pathway of the above molecules is anticipated to be via the initial labeling site, O-methyl, compared to the N-methyl group. Herein, we report the radiosynthesis of N-11CH3-MPC-6827 and N-11CH3-HD-800 and a comparison of their in vivo binding with the corresponding O-11CH3 analogues using microPET imaging and biodistribution methods. Both O-11CH3 and N-11CH3 labeled MT tracers exhibit high specific binding and brain. The N-11CH3 labeled PET ligands demonstrated similar in vivo binding characteristics compared with the corresponding O-11CH3 labeled tracers, [11C]MPC-6827 and [11C]HD-800 respectively.

Altered amygdala subregion-related circuits in treatment-naïve post-traumatic stress disorder comorbid with major depressive disorder.

Individuals with both post-traumatic stress disorder and major depressive disorder (PTSD+MDD) often show greater social and occupational impairment and poorer treatment response than individuals with PTSD alone. Increasing evidence reveals that the amygdala, a brain region implicated in the pathophysiology of both of these conditions, is a complex of structurally and functionally heterogeneous nuclei. Quantifying the functional connectivity of two key amygdala subregions, the basolateral (BLA) and centromedial (CMA), in PTSD+MDD and PTSD-alone could advance our understanding of the neurocircuitry of these conditions. 18 patients with PTSD+MDD, 28 with PTSD-alone, and 50 trauma exposed healthy controls (TEHC), all from a cohort who survived the same large earthquake in China, underwent resting-state functional magnetic resonance imaging. Bilateral BLA and CMA functional connectivity (FC) maps were created using a seed-based approach for each participant. The analysis of covariance of FC was used to determine between-group differences. A significant interaction between amygdala subregion and diagnostic group suggested that differences in connectivity patterns between the two seeds were mediated by diagnosis. Post-hoc analyses revealed that PTSD+MDD patients showed weaker connectivity between right BLA and (a) left anterior cingulate cortex/supplementary motor area, and (b) bilateral putamen/pallidum, compared with PTSD-alone patients. Higher CMA connectivities left ACC/SMA were also observed in PTSD+MDD compared with PTSD-alone. An inverse relationship between the connectivity of right BLA with right putamen/pallidum and MDD symptoms was found in PTSD+MDD. These findings indicate a relationship between the neural pathophysiology of PTSD+MDD compared with PTSD-alone and TEHC and may inform future clinical interventions.

Cognitive and emotional impairments underpinning suicidal activity in patients with mood disorders: an fMRI study.

OBJECTIVE: Mood disorders are strongly associated with suicide, the prevention of which is predicated on timely detection of suicidal activity (ideation, behaviour). Building on our previous work, we sought to determine the nature of neural responses to an emotional-cognitive task in patients with varying degrees of suicidal activity. METHOD: Seventy-nine patients with mood disorders were assessed clinically and scanned using fMRI. Neural responses to an Emotional Face-Word Stroop task were compared with 66 healthy controls. We identified regions of interest from seven key networks and examined responses to incongruent stimuli (Happy face-'Sad' word; Sad face-'Happy' word). RESULTS: In comparison with healthy controls, patients had differential activity during both incongruent conditions. When examining for associations with suicidal activity within the patient group, those with higher scores had decreased default mode network activity for Happy face-'Sad' word manipulation, and increased basal ganglia network activity for Sad face-'Happy' word manipulation, after controlling for patient characteristics. CONCLUSION: The fMRI findings suggest that suicidal activity in patients with mood disorders may be underpinned by cognitive-emotional deficits. These findings have implications for future suicide research and for achieving a deeper understanding of suicidal activity that may ultimately inform clinical detection and management.

Characterization of lipid rafts in human platelets using nuclear magnetic resonance: A pilot study.

Lipid microdomains ('lipid rafts') are plasma membrane subregions, enriched in cholesterol and glycosphingolipids, which participate dynamically in cell signaling and molecular trafficking operations. One strategy for the study of the physicochemical properties of lipid rafts in model membrane systems has been the use of nuclear magnetic resonance (NMR), but until now this spectroscopic method has not been considered a clinically relevant tool. We performed a proof-of-concept study to test the feasibility of using NMR to study lipid rafts in human tissues. Platelets were selected as a cost-effective and minimally invasive model system in which lipid rafts have previously been studied using other approaches. Platelets were isolated from plasma of medication-free adult research participants (n=13) and lysed with homogenization and sonication. Lipid-enriched fractions were obtained using a discontinuous sucrose gradient. Association of lipid fractions with GM1 ganglioside was tested using HRP-conjugated cholera toxin B subunit dot blot assays. 1H high resolution magic-angle spinning nuclear magnetic resonance (HRMAS NMR) spectra obtained with single-pulse Bloch decay experiments yielded spectral linewidths and intensities as a function of temperature. Rates of lipid lateral diffusion that reported on raft size were measured with a two-dimensional stimulated echo longitudinal encode-decode NMR experiment. We found that lipid fractions at 10-35% sucrose density associated with GM1 ganglioside, a marker for lipid rafts. NMR spectra of the membrane phospholipids featured a prominent 'centerband' peak associated with the hydrocarbon chain methylene resonance at 1.3 ppm; the linewidth (full width at half-maximum intensity) of this 'centerband' peak, together with the ratio of intensities between the centerband and 'spinning sideband' peaks, agreed well with values reported previously for lipid rafts in model membranes. Decreasing temperature produced decreases in the 1.3 ppm peak intensity and a discontinuity at ~18 °C, for which the simplest explanation is a phase transition from Ld to Lo phases indicative of raft formation. Rates of lateral diffusion of the acyl chain lipid signal at 1.3 ppm, a quantitative measure of microdomain size, were consistent with lipid molecules organized in rafts. These results show that HRMAS NMR can characterize lipid microdomains in human platelets, a methodological advance that could be extended to other tissues in which membrane biochemistry may have physiological and pathophysiological relevance.

Psychological autopsy of seventy high school suicides: Combined qualitative/quantitative approach.

OBJECTIVE: Suicide is the leading cause of death among Israeli youths but data on causes are scarce. This study used psychological autopsies of 70 Israeli school students who committed suicide during 2004-2011, attempting to determine the causes. METHODS: Four narratives of the self were identified (qualitative analysis) and compared (quantitative analysis): (1) regressive: functioning and mood deteriorated continuously (45%); (2) tragic: doing well until rapid decline around suicidal crisis (20%); (3) unstable: peaks and crises throughout life (20%); and (4) stable: long lasting state of adverse living circumstances (15%). Functioning, mental disorders, stressful life events and substance abuse were examined. RESULTS: A representative profile of the suicide-completer emerged. Suicidality in the tragic narrative involved shorter crisis, fewer risk factors and less psychopathology than the other narratives, also better general functioning and better school performance. Though decrease in functioning was evident in all groups, in the tragic group it tended to be disregarded. CONCLUSION: This study presents an in-depth analysis of a unique suicide population of high school students. A combined methodology of qualitative and quantitative analyses reveals a distinct subpopulation of suicidal adolescents with little or no overt psychopathology that poses a challenge to suicide prevention strategies.

Self-Rated Depression Severity Relative to Clinician-Rated Depression Severity: Trait Stability and Potential Role in Familial Transmission of Suicidal Behavior.

Self-rated depression and hopelessness severity are predictors of suicide attempt in major depression. This study evaluated whether: (1) greater self-rated distress relative to severity of clinician-rated depression is a trait; (2) that trait is familial; and (3) that trait is linked to familial transmission of suicidal behavior. A total of 285 mood disorder probands and 457 offspring were assessed twice, at least 1 year apart. Family and subject intra-class correlations for self-report depression and hopelessness, controlling for clinician-rated depression severity, were computed. Mixed general linear models determined offspring-proband correlations. Within-individual intra-class correlation (ICC) for depression-hopelessness was 37.8% (bootstrap 95% CI: 31.0-46.3%). Parent-offspring ICC was 10.7% (bootstrap 95% CI: 3.5-17.8%). Suicide attempt concordant parent-offspring correlation for subjective depression was positive, but negative for attempter parent and nonattempter offspring (p = .0213 for slope interaction). Pessimism was greater in proband or offspring attempters than proband or offspring nonattempters (p < .05). Self-reported hopelessness is partly trait-dependent, and there is modest familial transmission of self-reported depression linked to suicidal behavior that may partly explain familial transmission of suicidal behavior.

Further evidence of low baseline cortisol levels in suicide attempters.

BACKGROUND: Many, but not all studies of suicide attempters' cortisol response to stress-either social stress or pharmacological challenge-report an exaggerated response. Recent studies of resting baseline cortisol in past suicide attempters, however, have found lower baseline levels. METHODS: In this study, baseline salivary cortisols were obtained prior to a stress procedure from adults with lifetime diagnoses of a mood disorder (N=69), 31.9% of whom had made a prior suicide attempt. Data were collected during the piloting of this stress procedure, at various times of day and with/without an additional confederate in the room. RESULTS: Adjusting for procedural, demographic and clinical variables that affect salivary cortisol levels-including time of day of sampling, order of procedure with respect to other assessments, past alcohol abuse, current medication use, and bipolar diagnosis-past suicide attempters had lower baseline cortisol levels compared to non-attempters. LIMITATIONS: This is a pilot study with modest sample sizes using statistical, rather than experimental control of numerous variables affecting salivary cortisol levels. CONCLUSIONS: Results confirm previous studies. Low baseline cortisol levels have been associated with childhood adversity and externalizing disorders, suggesting a potential role in reducing inhibitions for risky and dangerous behaviors. Further research is needed to more fully characterize these associations and their role in suicidal behavior risk.

Isoform-level brain expression profiling of the spermidine/spermine N1-Acetyltransferase1 (SAT1) gene in major depression and suicide.

Low brain expression of the spermidine/spermine N-1 acetyltransferase (SAT1) gene, the rate-limiting enzyme involved in catabolism of polyamines that mediate the polyamine stress response (PSR), has been reported in depressed suicides. However, it is unknown whether this effect is associated with depression or with suicide and whether all or only specific isoforms expressed by SAT1, such as the primary 171 amino acid protein-encoding transcript (SSAT), or an alternative splice variant (SSATX) that is involved in SAT1 regulated unproductive splicing and transcription (RUST), are involved. We applied next generation sequencing (RNA-seq) to assess gene-level, isoform-level, and exon-level SAT1 expression differences between healthy controls (HC, N = 29), DSM-IV major depressive disorder suicides (MDD-S, N = 21) and MDD non-suicides (MDD, N = 9) in the dorsal lateral prefrontal cortex (Brodmann Area 9, BA9) of medication-free individuals postmortem. Using small RNA-seq, we also examined miRNA species putatively involved in SAT1 post-transcriptional regulation. A DSM-IV diagnosis was made by structured interview. Toxicology and history ruled out recent psychotropic medication. At the gene-level, we found low SAT1 expression in both MDD-S (vs. HC, p = 0.002) and MDD (vs. HC, p = 0.002). At the isoform-level, reductions in MDD-S (vs. HC) were most pronounced in four transcripts including SSAT and SSATX, while reductions in MDD (vs. HC) were pronounced in three transcripts, one of which was reduced in MDD relative to MDD-S (all p < 0.1 FDR corrected). We did not observe evidence for differential exon-usage (i.e. splicing) nor differences in miRNA expression. Results replicate the finding of low SAT1 brain expression in depressed suicides in an independent sample and implicate low SAT1 brain expression in MDD independent of suicide. Low expressions of both SSAT and SATX isoforms suggest that shared transcriptional mechanisms involved in RUST may account for low SAT1 brain expression in depressed suicides. Future studies are required to understand the functions and regulation of SAT1 isoforms, and how they relate to the pathogenesis of MDD and suicide.

Toward noninvasive quantification of brain radioligand binding by combining electronic health records and dynamic PET imaging data.

Quantitative analysis of positron emission tomography (PET) brain imaging data requires a metabolite-corrected arterial input function (AIF) for estimation of distribution volume and related outcome measures. Collecting arterial blood samples adds risk, cost, measurement error, and patient discomfort to PET studies. Minimally invasive AIF estimation is possible with simultaneous estimation (SIME), but at least one arterial blood sample is necessary. In this study, we describe a noninvasive SIME (nSIME) approach that utilizes a pharmacokinetic input function model and constraints derived from machine learning applied to an electronic health record database consisting of "long tail" data (digital records, paper charts, and handwritten notes) that were collected ancillary to the PET studies. We evaluated the performance of nSIME on 95 [(11)C]DASB PET scans that had measured AIFs. The results indicate that nSIME is a promising alternative to invasive AIF measurement. The general framework presented here may be expanded to other metabolized radioligands, potentially enabling quantitative analysis of PET studies without blood sampling. A glossary of technical abbreviations is provided at the end of this paper.

Pathways of polyunsaturated fatty acid utilization: implications for brain function in neuropsychiatric health and disease.

Essential polyunsaturated fatty acids (PUFAs) have profound effects on brain development and function. Abnormalities of PUFA status have been implicated in neuropsychiatric diseases such as major depression, bipolar disorder, schizophrenia, Alzheimer's disease, and attention deficit hyperactivity disorder. Pathophysiologic mechanisms could involve not only suboptimal PUFA intake, but also metabolic and genetic abnormalities, defective hepatic metabolism, and problems with diffusion and transport. This article provides an overview of physiologic factors regulating PUFA utilization, highlighting their relevance to neuropsychiatric disease.

Intact alternation performance in high lethality suicide attempters.

Suicide attempters often perform poorly on tasks linked to ventral prefrontal cortical (VPFC) function. Object Alternation (OA) - a VPFC probe - has not been used in these studies. In this study, currently depressed medication-free past suicide attempters whose most severe attempt was of high (n=31) vs. low (n=64) lethality, 114 medication-free depressed non-attempters, and 86 non-patients completed a computerized OA task. Participants also completed comparison tasks assessing the discriminant validity of OA (Wisconsin Card Sort), its concurrent validity relative to tasks associated with past attempt status (computerized Stroop task, Buschke Selective Reminding Test), and its construct validity as a VPFC measure (Go-No Go and Iowa Gambling Task). Against expectations, high lethality suicide attempters - the majority of whom used non-violent methods in their attempts with some planning - outperformed other depressed groups on OA, with no group differences observed on Wisconsin Card Sort. Despite intact performance on OA, past attempters exhibited deficits on the Stroop and Buschke. OA performance was associated with performance on Go-No Go and Iowa Gambling, confirming that OA measures a similar construct. VPFC dysfunction may not be a characteristic of all suicide attempters, especially those who make more carefully planned, non-violent - though potentially lethal - attempts.

Transitions in the transcriptome of the serotonergic and dopaminergic systems in the human brain during adolescence.

Adolescence is a period of profound neurophysiological, behavioral, cognitive and psychological changes, but not much is known about the underlying molecular neural mechanisms. The aim of this study was to systematically analyze expression levels of the genes forming serotonergic and dopaminergic synapses during adolescence. We analyzed the mRNA expression profiles of genes that code for all components of serotonergic and dopaminergic synapses, in 16 brain areas from human and non-human primates from public domain databases, to detect genes whose expression changes during adolescence. Two serotonin receptors, HTR1E and HTR1B had expression levels that exhibit a sharp transition in the prefrontal cortex in adolescence, but we found no similar transition in the dopaminergic system. A similar but smoother rise in expression levels is observed in HTR4 and HTR5A, and in HTR1E and HTR1B in three other expression datasets published. An earlier rise is observed in HTR1A, and a smooth and significant rise with age is observed in the expression of HTR1E in microarray measurements in macaque monkeys. The expression of HTR1E and HTR1B is correlated across subjects within each age group, suggesting that they are controlled by common mechanisms. These results point to HTR1E and HTR1B as major candidate genes involved in adolescence maturation processes, and to their operation through common control mechanisms. The maturation profiles may also involve several other 5-HT receptors, including the genes HTR5A, HTR4 and HTR1A.

Synthesis and in vitro evaluation of [18F]BMS-754807: a potential PET ligand for IGF-1R.

Radiosynthesis and in vitro evaluation of [(18)F](S)-1-(4-((5-cyclopropyl-1H-pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide ([(18)F]BMS-754807 or [(18)F]1) a specific IGF-1R inhibitor was performed. [(18)F]1 demonstrated specific binding in vitro to human cancer tissues. Synthesis of reference standard 1 and corresponding bromo derivative (1a), the precursor for radiolabeling were achieved from 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine (4) in three steps with 50% overall yield. The radioproduct was obtained in 8% yield by reacting 1a with [(18)F]TBAF in DMSO at 170°C at high radiochemical purity and specific activity (1-2Ci/µmol, N=10). The proof of concept of IGF-IR imaging with [(18)F]1 was demonstrated by in vitro autoradiography studies using pathologically identified surgically removed grade IV glioblastoma, breast cancer and pancreatic tumor tissues. These studies indicate that [(18)F]1 can be a potential PET tracer for monitoring IGF-1R.

Iowa gambling task performance in currently depressed suicide attempters.

Deficits in decision-making using the Iowa Gambling Task (IGT) have been found in past suicide attempters, but primarily euthymic and/or medicated patients. This study compared IGT performance among medication-free, currently depressed patients (unipolar and bipolar) with (n=26) and without (n=46) a past history of suicide attempt, and healthy volunteers (n=42). Attempter status, in a sample whose attempts were predominantly non-violent, was not associated with impaired IGT performance even when accounting for sex, mood disorder type, and comorbid Borderline Personality Disorder. A non-significant trend towards poorer performance was found in a small subgroup of past attempters who had used a violent method, consistent with prior studies. Suicide intent and ideation were unrelated to IGT scores. There were no consistent associations between IGT performance and ratings of impulsiveness (Barratt Impulsiveness Scale (BIS)), hostility (Buss-Durkee Hostility Inventory (BDHI)) or aggression (Brown-Goodwin Aggression Inventory (BGAI)). Results suggest that decision-making impairment is related to specific subtypes of suicidal behavior, but may not be universally sensitive to suicide risk in all types of attempters, especially those using non-violent means. Psychometric and conceptual issues surrounding the IGT also appear to affect its utility as a general marker of suicidal behavior risk.

Hippocampal granule neuron number and dentate gyrus volume in antidepressant-treated and untreated major depression.

Smaller hippocampal volume is reported in major depressive disorder (MDD). We hypothesize that it may be related to fewer granule neurons (GN) in the dentate gyrus (DG), a defect possibly reversible with antidepressants. We studied age-, sex-, and postmortem interval-matched groups: no major psychopathology (controls); unmedicated-MDD; and MDD treated with serotonin reuptake inhibitors (MDD*SSRI) or tricyclics (MDD*TCA). Frozen right hippocampi were fixed, sectioned (50 µm), immunostained with neuronal nuclear marker (NeuN), and counterstained with hematoxylin. GN and glial number, and DG and granule cell layer (GCL) volumes were stereologically estimated. Fewer GNs in the anterior DG were present in unmedicated-MDDs compared with controls (p=0.013). Younger age of MDD onset correlated with fewer GNs (p=0.021). Unmedicated-MDDs had fewer mid-DG GNs than MDD*SSRIs (p=0.028) and controls (p=0.032). Anterior GCL glial number did not differ between groups. Anterior/mid GCL volume was smaller in unmedicated-MDDs vs controls (p=0.008) and larger in MDD*SSRIs vs unmedicated-MDDs (p<0.001), MDD*TCAs (p<0.001), and controls (p<0.001). Anterior GCL volume and GN number (r=0.594, p=0.001), and mid DG volume and GN number (r=0.398, p=0.044) were correlated. Anterior DG capillary density correlated with GN number (p=0.027), and with GCL (p=0.024) and DG (r=0.400, p=0.047) volumes. Posterior DG volume and GN number did not differ between groups. Fewer GNs in unmedicated-MDD without fewer neuronal progenitor cells, as previously reported, suggests a cell maturation or survival defect, perhaps related to MDD duration. This may contribute to a smaller hippocampus and is potentially reversed by SSRIs. Postmortem studies are correlative and animal studies are needed to test implied causal relationships.

Pilot randomized clinical trial of an SSRI vs bupropion: effects on suicidal behavior, ideation, and mood in major depression.

Randomized controlled trials in depressed patients selected for elevated suicidal risk are rare. The resultant lack of data leaves uncertainty about treatment in this population. This study compared a serotonin reuptake inhibitor with a noradrenergic/dopaminergic antidepressant in major depression with elevated suicidal risk factors. We conducted a double-blind, randomized, clinical pilot trial of paroxetine (N=36) or bupropion (N=38) in DSM IV major depression with a suicide attempt history or current suicidal ideation. The effects during acute (8 weeks) and continuation treatment (up to 16 weeks) were measured. Main outcomes were suicidal behavior and ideation. The secondary outcome was modified 17-item Hamilton Depression Rating Scale score subtracting the suicide item (mHDRS-17). Treatment was not associated with time to a suicidal event and no treatment main effect or treatment × time interaction on suicidal ideation or mHDRS-17 was found. Exploratory model selection showed modest advantages for paroxetine on: (1) mHDRS-17 (p=0.02); and (2) in a separate model adjusted for baseline depression, for suicidal ideation measured with the Beck Scale for Suicidal Ideation (p=0.03), with benefit increasing with baseline severity. Depressed patients with greater baseline suicidal ideation treated with paroxetine compared with bupropion appeared to experience greater acute improvement in suicidal ideation, after adjusting for global depression. Given the lack of evidence-based pharmacotherapy guidelines for suicidal, depressed patients-an important public health population-this preliminary finding merits further study.

Synthesis and in vivo evaluation of [O-methyl-11C] N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide as an imaging probe for 5-HT6 receptors.

The serotonin receptor 6 (5-HT(6)) is implicated in the pathophysiology of cognitive diseases, schizophrenia, anxiety and obesity and in vivo studies of this receptor would be of value for studying the pathophysiology of these disorders. Therefore, N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB399885), a selective and high affinity (pK(i)=9.11) 5-HT(6) antagonist, has been radiolabeled with carbon-11 by O-methylation of the corresponding desmethyl analogue with [(11)C]MeOTf in order to determine the suitability of [(11)C]SB399885 to quantify 5-HT(6)R in living brain using PET. Desmethyl-SB399885 was prepared, starting from 1-(2-methoxyphenyl) piperazine hydrochloride, in excellent yield. The yield obtained for radiolabeling of [(11)C]SB399885 was 30±5% (EOS) and the total synthesis time was 30min at EOB. PET studies with [(11)C]SB399885 in baboon showed fast uptake followed by rapid clearance in the brain. Highest uptake of radioactivity of [(11)C]SB399885 in baboon brain were found in temporal cortex, parahippocampal gyrus, pareital cortex, amygdala, and hippocampus. Poor brain entry and inconsistent brain uptake of [(11)C]SB399885 compared to known 5-HT(6)R distribution limits its usefulness for the in vivo quantification of 5-HT(6)R with PET.