Inverse changes in raphe and cortical 5-HT1B receptor availability after acute tryptophan depletion in healthy human subjects.

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 [11 C]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 [11 C]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 [11 C]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.

Test-retest reliability of the novel 5-HT1B receptor PET radioligand [11C]P943.

PURPOSE: [(11)C]P943 is a novel, highly selective 5-HT1B PET radioligand. The aim of this study was to determine the test-retest reliability of [(11)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 BPND 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 BPND, 0.5 % and 11.5 % for MA1 BPP, 16.7 % and 28.3 % for MA1 BPF, and between 0.2 % and 5.4 % for MRTM2 BPND. The power analyses showed a greater number of subjects were required using MA1 BPF compared with other outcome measures for both within-subject and between-subject study designs. ICC values were the highest using MRTM2 BPND and the lowest with MA1 BPF 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-HT1B receptor binding can be obtained using the novel PET radioligand [(11)C]P943. Quantification of 5-HT1B receptor binding with MRTM2 BPND and with MA1 BPP provided the least variability and optimal power for within-subject and between-subject designs.

Assessment of the Efficacy and Safety of BMS-820836 in Patients With Treatment-Resistant Major Depression: Results From 2 Randomized, Double-Blind Studies.

Two phase 2B, randomized, double-blind studies assessed the efficacy and safety of fixed or flexible dose of triple monoamine uptake inhibitor BMS-820836 in patients with treatment-resistant depression to demonstrate whether switching to BMS-820836 was superior to the continuation of standard antidepressant treatment. Patients with a history of inadequate response to 1 to 3 adequate trials of antidepressant therapies were prospectively treated with duloxetine 60 mg/d for 8 weeks (CN162-006) or duloxetine 60 mg/d or escitalopram 20 mg/d for 7 weeks (CN162-007). Inadequate responders were randomized to continue their prospective phase treatment or switch to flexible-dose (0.5-2 mg/d; CN162-006) or fixed-dose (0.25, 0.5, 1, or 2 mg/d; CN162-007) BMS-820836 for 6 weeks. The primary end point in both studies was mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from randomization to study end point. BMS-820836 flexible (0.5-2 mg/d) or fixed dose of 1 mg/d or greater showed efficacy similar to the continuation of antidepressant treatment, with no statistically significant or clinically meaningful differences. In the CN162-006 study, the adjusted mean (SE) change in MADRS total score was -8.7 (0.661) and -8.1 (0.656) for BMS-820836 and duloxetine, respectively (P = 0.526). In the CN162-007 study, the adjusted mean (SE) change in MADRS total score was -7.3 (0.830) and -6.6 (0.842) for BMS-820836 of 1 and 2 mg, respectively, and -6.9 (0.602) for the continuation group (P = 0.910). Thus, BMS-820836 was well tolerated, with no evidence of dose-dependent discontinuations due to adverse events, but it failed to demonstrate superiority to the continuation of an existing antidepressant in patients with treatment-resistant depression.

An HPA-1a-positive platelet-depleting agent for prevention of fetal and neonatal alloimmune thrombocytopenia: a randomized, single-blind, placebo-controlled, single-center, phase 1/2 proof-of-concept study.

BACKGROUND: Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a rare and potentially life-threatening bleeding disorder of the fetus/newborn. Antibodies against human platelet antigen 1a (HPA-1a) are associated with the most frequent FNAIT cases. There are no approved therapies for FNAIT prevention or treatment. RLYB211 is a polyclonal HPA-1a hyperimmune IgG being developed to prevent FNAIT. OBJECTIVES: To investigate whether a single dose of anti-HPA-1a (1000 IU) could markedly accelerate the elimination of HPA-1ab platelets transfused into healthy, HPA-1a-negative participants as compared with placebo. METHODS: This randomized, single-blind, placebo-controlled, single-center, phase 1/2 proof-of-concept study (EudraCT: 2019-003459-12) included HPA-1a- and HLA-A2-negative healthy men. Cohort 1 received intravenous RLYB211 or placebo 1 hour after transfusion of HPA-1ab platelets. Cohort 1B received RLYB211 or placebo, followed by platelet transfusion 1 week later. Primary endpoint was the half-life of transfused platelets in circulation after administration of RLYB211 or placebo, determined by flow cytometry. Proof of concept was ≥90% reduction of half-life relative to placebo. RESULTS: Twelve participants were allocated to cohort 1 or 1B and randomized to receive RLYB211 (n = 9) or placebo (n = 3). RLYB211 markedly accelerated the elimination of HPA-1ab platelets in all participants vs placebo. In cohort 1B, this effect was observed 7 days after RLYB211 administration. Two treatment-emergent adverse events were possibly related to treatment, both in RLYB211-treated participants. No participants developed HPA-1a antibodies at 12 or 24 weeks. CONCLUSION: These data support the hypothesis that anti-HPA-1a could be used as prophylaxis in women at risk of having an FNAIT-affected pregnancy.

Prefrontal cortical response to emotional faces in individuals with major depressive disorder in remission.

Abnormalities in the response of the orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) to negative emotional stimuli have been reported in acutely depressed patients. However, there is a paucity of studies conducted in unmedicated individuals with major depressive disorder in remission (rMDD) to assess whether these are trait abnormalities. To address this issue, 19 medication-free rMDD individuals and 20 healthy comparison (HC) participants were scanned using functional magnetic resonance imaging while performing an implicit emotion processing task in which they labeled the gender of faces depicting negative (fearful), positive (happy) and neutral facial expressions. The rMDD and HC groups were compared using a region-of-interest approach for two contrasts: fear vs. neutral and happy vs. neutral. Relative to HC, rMDD showed reduced activation in left OFC and DLPFC to fearful (vs. neutral) faces. Right DLPFC activation to fearful (vs. neutral) faces in the rMDD group showed a significant positive correlation with duration of euthymia. The findings support deficits in left OFC and DLPFC responses to negative emotional stimuli during euthymic periods of MDD, which may reflect trait markers of the illness or a 'scar' due to previous depression. Recovery may also be associated with compensatory increases in right DLPFC functioning.

Benefit-risk assessment and reporting in clinical trials of chronic pain treatments: IMMPACT recommendations.

ABSTRACT: Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit-risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit-risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit-risk should be combined at the level of the individual patient, when possible, in addition to the benefit-risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit-risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results.

Time course of regional brain activity accompanying auditory verbal hallucinations in schizophrenia.

BACKGROUND: The pathophysiology of auditory verbal hallucinations remains poorly understood. AIMS: To characterise the time course of regional brain activity leading to auditory verbal hallucinations. METHOD: During functional magnetic resonance imaging, 11 patients with schizophrenia or schizoaffective disorder signalled auditory verbal hallucination events by pressing a button. To control for effects of motor behaviour, regional activity associated with hallucination events was scaled against corresponding activity arising from random button-presses produced by 10 patients who did not experience hallucinations. RESULTS: Immediately prior to the hallucinations, motor-adjusted activity in the left inferior frontal gyrus was significantly greater than corresponding activity in the right inferior frontal gyrus. In contrast, motor-adjusted activity in a right posterior temporal region overshadowed corresponding activity in the left homologous temporal region. Robustly elevated motor-adjusted activity in the left temporal region associated with auditory verbal hallucinations was also detected, but only subsequent to hallucination events. At the earliest time shift studied, the correlation between left inferior frontal gyrus and right temporal activity was significantly higher for the hallucination group compared with non-hallucinating patients. CONCLUSIONS: Findings suggest that heightened functional coupling between the left inferior frontal gyrus and right temporal regions leads to coactivation in these speech processing regions that is hallucinogenic. Delayed left temporal activation may reflect impaired corollary discharge contributing to source misattribution of resulting verbal images.

Assessing the sensitivity of [¹¹C]p943, a novel 5-HT1B radioligand, to endogenous serotonin release.

The main objective of the current study was to determine the sensitivity of the positron emission tomography (PET) radioligand [¹¹C]P943 to fenfluramine-induced changes in endogenous 5-HT in nonhuman primate brain. Fenfluramine-induced changes in 5-HT(1B) occupancy were compared to those obtained by self-block with unlabeled P943. Two baboons and 1 rhesus monkey were given preblocking or displacing doses of fenfluramine (1-5 mg/kg) or preblocking doses of unlabeled P943 (0.2 mg/kg) and imaged with [¹¹C]P943 PET. Receptor occupancy by the low dose of fenfluramine (1 mg/kg) in the baboons was 25 and 29% and by the high dose of fenfluramine (5 mg/kg) in the rhesus macaque was 42%. Receptor occupancy by P943 (0.2 mg/kg) was 68 and 86% in the baboons. PET imaging of 5-HT(1B) receptors with [¹¹C]P943 may be a useful approach for measuring changes in endogenous 5-HT in the living human brain.

Citalopram reduces endotoxin-induced fatigue.

Increased levels of inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-6 (IL-6) may play a role in depression. Mild depressive-like symptoms can be induced in humans through activation of the innate immune system with endotoxin. Whether preventive treatment with antidepressants can reduce endotoxin-induced symptoms has never been tested. In a double-blind, randomized, placebo-controlled, cross-over study, we administered intravenous low-dose endotoxin (0.8 ng/kg) or placebo to 11 healthy subjects who had received oral pre-treatment with citalopram (10 mg twice a day) or placebo for 5 days. The Montgomery-Åsberg Depression Rating Scale, the State and Trait Anxiety Inventory, and a visual analog scale were used to measure depressive and anxiety symptoms and social anhedonia. Serum levels of TNF and IL-6 were measured with immunoassays. Compared to placebo, endotoxin administration increased serum levels of TNF and IL-6, and caused mild depressive-like symptoms, in particular lassitude and social anhedonia. While citalopram pre-treatment had no effect on the innate immune response to endotoxin, it reduced the endotoxin-induced MADRS total score by 50%, with a moderate effect size (Cohen's d=0.5). Most of the MADRS total score was due to the lassitude item, and citalopram pre-treatment specifically reduced endotoxin-induced lassitude with a large effect size (Cohen's d=0.9). These results suggest that subchronic pre-treatment with the serotonin-reuptake inhibitor citalopram blunts mood symptoms induced by acute immune system activation with endotoxin without inhibiting the peripheral immune response.

Enhanced visual motion perception in major depressive disorder.

Major depressive disorder (MDD) is a mood disorder that is not traditionally considered to affect the visual system. However, recent findings have reported decreased cortical levels of the inhibitory neurotransmitter GABA in occipital cortex. To explore possible functional consequences of MDD on visual processing, we applied a psychophysical visual motion processing task in which healthy young adults typically exhibit impaired perceptual discrimination of large high-contrast stimuli. It has been suggested that this phenomenon, spatial suppression, is mediated by GABAergic center-surround antagonism in visual pathways. Based on previous findings linking MDD to occipital GABA dysfunction, we hypothesized that MDD patients would exhibit decreased spatial suppression, leading to the counterintuitive hypothesis of better psychophysical performance. Indeed, motion perception for typically suppressed stimuli was enhanced in patients with MDD compared with age-matched controls. Furthermore, the degree of spatial suppression correlated with an individual's illness load; patients with greater lifetime duration of depression exhibited the least spatial suppression and performed the best in the high-contrast motion discrimination task. Notably, this decrease in spatial suppression persisted beyond recovery and without the confound of acute illness or treatment; all patients had been clinically recovered and unmedicated for several months at the time of testing, suggesting that depression has ubiquitous consequences that may persist long after mood symptoms have receded. This finding raises the possibility that spatial suppression may represent a sensitive endophenotypic marker of trait vulnerability in MDD.

Simplified quantification of 5-HT2A receptors in the human brain with [11C]MDL 100,907 PET and non-invasive kinetic analyses.

BACKGROUND: [(11)C]MDL100,907 is a promising positron emission tomography (PET) ligand for 5-HT(2A) receptor quantification in vivo. Studies suggest that [(11)C]MDL100,907 PET may be quantified by non-invasive reference tissue analyses using cerebellum as reference region. We systematically investigated the validity of such analyses. METHODS: Five healthy volunteers underwent [(11)C]MDL100,907 PET at baseline and after mirtazapine pre-treatment. Regional time-activity curves of 10 regions of interest (ROI) were analyzed for binding potential (BP(ND)) and mirtazapine receptor occupancy (Occ) using: simplified reference tissue model (SRTM), multi-linear reference tissue model (MRTM), their two-parameter versions (SRTM2/MRTM2), non-invasive graphical analysis (NIGA) and a tissue activity concentration ratio. NIGA was also applied voxel-wise to generate BP(ND) maps. These methods were compared with a two-tissue compartment model with arterial input function (2TCM) Results: SRTM and MRTM frequently failed to yield reliable results. SRTM2 and MRTM2 gave virtually identical estimates of BP(ND), which were highly correlated with 2TCM analyses (R(2)>or=0.86) although with negative bias (-29+/-27% at baseline across all ROI). NIGA was less biased (-19+/-16%) and better correlated with 2TCM (R(2)>or=0.93). Regarding Occ, NIGA and SRTM2/MRTM2 showed comparable mean biases (-11+/-27% vs. -7+/-47%) but correlation with 2TCM was higher for NIGA (R(2)=0.90 vs. 0.77). NIGA parametric maps (analysed using identical ROI) resulted in moderate bias in BP(ND) (-26+/-22%; R(2)>or=0.88) and Occ (-17+/-36%; R(2)=0.78). Estimates obtained from tissue ratios performed least favourably. CONCLUSIONS: NIGA is well suited for analysis of [(11)C]MDL100,907 PET studies, yielding estimates of 5-HT(2A) receptor availability and changes that are highly correlated with results from invasive 2TCM analyses. This should greatly enhance the applicability of 5-HT(2A) receptor PET studies.

Increased peripheral blood expression of electron transport chain genes in bipolar depression.

OBJECTIVE: To identify specific genetic pathways showing altered expression in peripheral blood of depressed subjects with bipolar disorder (BPD). METHODS: Illumina Sentrix BeadChip (Human-6v2) microarrays containing >48,000 transcript probes were used to measure levels of gene expression in peripheral blood from 20 depressed subjects with BPD and in 15 healthy control subjects. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) was used to confirm a subset of these differences. RESULTS: A total of 1,180 genes were differentially expressed between subjects with BPD and healthy controls (fold-change >1.3, false discovery rate-corrected p < 0.05, covaried for age and sex). Of these, 559 genes were up-regulated in BPD subjects and 621 were down-regulated. Surprisingly, there was no difference between medicated (n = 11) and unmedicated (n = 9) subjects with BPD for any of these genes. Pathway analysis using GeneGo MetaCore software showed that the most significantly affected pathway was the mitochondrial electron transport chain (ETC). Of the 85 objects (genes or proteins) in this pathway, 22 were up-regulated and 2 down-regulated in subjects with BPD. qRT-PCR confirmed up-regulation of nuclear encoded ETC genes in complexes I, III, IV, and V and, in addition, demonstrated up-regulation of mitochondrially encoded genes in each of these complexes. CONCLUSION: These results suggest that increased expression of multiple components of the mitochondrial ETC may be a primary deficit in bipolar depression, rather than an effect of medication.

A sequencing-based survey of functional APAF1 alleles in a large sample of individuals with affective illness and population controls.

Rare apoptosis-promoting functional variants in the apoptosis protease activating factor 1 (APAF1) gene were recently reported to co-segregate with major depression in male members of families from Utah. In order to estimate the impact of these variants on risk for major depressive disorder (MDD) in the general population, we surveyed the frequency of the APAF1 putative MDD risk alleles using re-sequencing in a large sample of northern European and European-American subjects, including a large number of males with MDD. The E777K and N782T APAF1 variants previously described by Harlan et al. [Harlan et al. (2006) Mol Psychiatry 11(1):76-85] were found at low frequencies in affected individuals and population controls. The C450W and Q465R variants were not detected in any of the 632 subjects sequenced. These results show that the APAF1 variants associated with risk for MDD in the Utah pedigrees are very rare in Northern European and European-American populations. In addition, the E777K and N782T variants were found at low frequencies both in patients and population controls, suggesting that these variants have limited impact on risk for MDD.

Interpretation of chronic pain clinical trial outcomes: IMMPACT recommended considerations.

Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.

Lamotrigine-associated rash: to rechallenge or not to rechallenge?

The major burden of illness in bipolar disorder (BD) is in the depressive pole. Lamotrigine has been shown to be useful in the long-term prophylaxis of depressive episodes in BD. Current guidelines recommend discontinuing lamotrigine in patients who develop rash. Our objective in this paper is to review literature to identify possible predictors of serious vs. benign rash that might help guide clinical decision-making and recommend titration strategy for re-introduction of lamotrigine, if indicated. We performed a search of the literature between 1966 and July 2008 to investigate the phenomenon of lamotrigine-induced rash and rechallenge procedures. The search identified six reports, and we were able to identify another case series from reviewing the bibliography of all of the above papers. We reviewed all the papers of lamotrigine rash rechallenge that resulted from the literature search. These papers describe 44 cases of lamotrigine rechallenge. Currently, there are 39 reported cases in the literature of successful lamotrigine rechallenge after a rash and five cases with rash recurrence. There are some characteristics of the rash that can help identify serious cases from benign ones. In addition, very slow titration of lamotrigine is crucial to the reduction of rash recurrence rate. Several cases that develop benign rash on lamotrigine can be rechallenged without adverse consequences. We believe that lamotrigine rechallenge in bipolar depression is an under-utilized option in our clinical armamentarium, and further studies are needed to guide us in this area.

Brain serotonin transporter binding in former users of MDMA ('ecstasy').

BACKGROUND: Animal experimental studies have prompted concerns that widespread use of 3,4-methylenedioxymethamphetamine (MDMA; 'ecstasy') by young people may pose a major public health problem in terms of persistent serotonin neurotoxicity. AIMS: To determine the status of brain serotonin neurons in a group of abstinent MDMA users. METHOD: We assessed the integrity of brain serotonin neurons by measuring serotonin transporter (SERT) binding using positron emission tomography (PET) and [(11)C]DASB in 12 former MDMA users, 9 polydrug users who had never taken MDMA and 19 controls who reported no history of illicit drug use. RESULTS: There was no significant difference in the binding potential of [(11)C]DASB between the groups in any of the brain regions examined. CONCLUSIONS: To the extent that [(11)C]DASB binding provides an index of the integrity of serotonin neurons, our findings suggest that MDMA use may not result in long-term damage to serotonin neurons when used recreationally in humans.

Neural correlates of impulse control during stop signal inhibition in cocaine-dependent men.

Altered impulse control is associated with substance use disorders, including cocaine dependence. We sought to identify the neural correlates of impulse control in abstinent male patients with cocaine dependence (PCD). Functional magnetic resonance imaging (fMRI) was conducted during a stop signal task that allowed trial-by-trial evaluation of response inhibition. Fifteen male PCD and 15 healthy control (HC) subjects, matched in age and years of education, were compared. Stop signal reaction time (SSRT) was derived on the basis of a horse race model. By comparing PCD and HC co-varied for stop success rate, task-related frustration rating, and post-error slowing, we isolated the neural substrates of response inhibition, independent of attentional monitoring (of the stop signal) and post-response processes including affective responses and error monitoring. Using region of interest analysis, we found no differences between HC and PCD who were matched in stop signal performance in the pre-supplementary motor area (pre-SMA) previously shown to be associated with SSRT. However, compared with HC, PCD demonstrated less activation of the rostral anterior cingulate cortex (rACC), an area thought to be involved in the control of stop signal inhibition. The magnitude of rACC activation also correlated negatively with the total score and the impulse control subscore of the Difficulty in Emotion Regulation Scale in PCD. The current study thus identified the neural correlates of altered impulse control in PCD independent of other cognitive processes that may influence stop signal performance. Relative hypoactivation of the rACC during response inhibition may represent a useful neural marker of difficulties in impulse control in abstinent cocaine-dependent men who are at risk of relapse.

Inflammation, glutamate, and glia in depression: a literature review.

Multiple lines of evidence suggest that inflammation and glutamate dysfunction contribute to the pathophysiology of depression. In this review we provide an overview of how these two systems may interact. Excess levels of inflammatory mediators occur in a subgroup of depressed patients. Studies of acute experimental activation of the immune system with endotoxin and of chronic activation during interferon-alpha treatment show that inflammation can cause depression. Peripheral inflammation leads to microglial activation which could interfere with excitatory amino acid metabolism leading to inappropriate glutamate receptor activation. Loss of astroglia, a feature of depression, upsets the balance of anti- and pro-inflammatory mediators and further impairs the removal of excitatory amino acids. Microglia activated by excess inflammation, astroglial loss, and inappropriate glutamate receptor activation ultimately disrupt the delicate balance of neuroprotective versus neurotoxic effects in the brain, potentially leading to depression.

Presentations of psychosis with violence: variations in different jurisdictions. A comparison of patients with psychosis in the high security hospitals of Scotland and England.

BACKGROUND: International literature is consistent on there being a significant relationship between psychosis and violence, less so on its extent and nature, but two main presentational types are increasingly recognized. In one, people are unremarkable before onset of illness and psychotic symptoms commonly drive violence; in the other, psychosis is preceded by childhood conduct problems, associated with personality disorder, and psychotic symptoms seem less relevant. AIMS: To explore the extent to which variations in aspects of social and service context in different jurisdictions affect presentational type among people admitted to high security hospitals. HYPOTHESES: There will be differences between jurisdictions in proportions of patients with pure psychosis or with psychosis and antecedent personality disorder, but symptom drive to violence will be more common in the pure psychosis group regardless of social, legal and service context. METHOD: Independently conducted record studies were used to compare high security hospital patients with psychosis in Scotland and England, all resident between 25 August 1992 and 13 August 1993. RESULTS: The cohorts were similar in offence histories, predominance of schizophrenia, age at first hospitalization for psychosis and first high security hospitalization. More Scottish patients had co-morbid substance misuse diagnoses and/or personality disorder than patients in England. Psychotic symptom drive to the index offence was, however, four times more likely in the pure psychosis groups, regardless of sex, ethnic group or country. Scottish patients spent less time in high security after the index act. CONCLUSIONS: Our hypotheses were sustained. Knowledge about lifestyle before onset of psychosis is important for interpreting literature on how psychotic symptoms relate to violence. This may also influence longer term outcome, although the shorter length of secure hospital stay in Scotland was perhaps affected more by greater availability of open 'step-down' beds.

Reduction in occipital cortex gamma-aminobutyric acid concentrations in medication-free recovered unipolar depressed and bipolar subjects.

BACKGROUND: Studies using proton magnetic resonance spectroscopy (MRS) have indicated that unmedicated, acutely depressed patients have decreased levels of gamma-aminobutyric acid (GABA) in occipital cortex. Cortical levels of glutamate (Glu) may be increased, although these data are less consistent. The aim of this study was to use MRS to determine whether changes in GABA and Glu levels were present in patients with mood disorders who had recovered and were no longer taking medication. METHODS: An [1H]-MRS was used to measure levels of GABA, of the combined concentration of Glu and glutamine (Gln), and of N-acetylaspartate (NAA) in occipital cortex in medication-free, fully recovered subjects with a history of recurrent unipolar depression (n = 15), bipolar disorder (n = 16), and a group of healthy controls (n = 18). RESULTS: Occipital levels of GABA and NAA were significantly lower in recovered depressed and bipolar subjects than in healthy controls, whereas Glu +Gln concentrations were higher. CONCLUSIONS: Our data suggest that recovered unmedicated subjects with a history of mood disorder have changes in cortical concentrations of GABA, NAA, and Glu +Gln. These biochemical abnormalities may be markers of a trait vulnerability to mood disorder, rather than neurochemical correlates of an abnormal mood state.