Beata R. Godlewska

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen’s d=−0.14, % difference=−1.24). This effect was driven by patients with recurrent MDD (Cohen’s d=−0.17, % difference=−1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen’s d=−0.20, % difference=−1.85) and a trend toward smaller amygdala (Cohen’s d=−0.11, % difference=−1.23) and larger lateral ventricles (Cohen’s d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

The effect of the serotonin transporter polymorphism (5-HTTLPR) on amygdala function: a meta-analysis.

The 5-HTTLPR polymorphism has been widely regarded as a potential genetic risk factor for affective disorders. Consistent with this, this polymorphism has been associated with altered amygdala responses at rest and in response to aversive stimuli. However, the strength of this association remains uncertain. We sought to synthesize existing data on the association between the 5-HTTLPR polymorphism and amygdala activation and ascertain the strength of evidence for this association. Meta-analytic techniques were applied to data from relevant published studies and unpublished data sets to obtain an estimate of the likely magnitude of effect of any association. The large number of studies allowed us to apply a formal test of publication bias, as well as explore the impact of various study-level characteristics on the magnitude of the observed effect size. Our meta-analysis indicated that there is a statistically significant but small effect of 5-HTTLPR on left and right amygdala activity. However, there was considerable between-study heterogeneity, which could not be fully accounted for by the study design and sample characteristics that we investigated. In addition, there was evidence of excess statistical significance among published studies. These findings indicate that the association between the 5-HTTLPR and amygdala activation is smaller than originally thought, and that the majority of previous studies have been considerably under powered to reliably demonstrate an effect of this size.

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen’s d effect sizes: −0.10 to −0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: −0.26 to −0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

D-amino acid oxidase activity and expression are increased in schizophrenia

D-amino acid oxidase (DAO, DAAO) metabolises the NMDA receptor (NMDAR) modulator D-serine.1 Enhanced DAO activity is thus a potential cause of reduced D-serine and thence impaired NMDAR functioning in schizophrenia,2 and an explanation for the genetic contribution that DAO may make to the disorder.3,4 Here we report that DAO activity, and expression, are increased in the cerebellum in schizophrenia, but not in bipolar disorder, and are not related to SNPs in DAO or its putative activator gene G72/G30.3 n nWe measured DAO enzyme activity, and DAO mRNA by qRT-PCR, using established methods, in cerebellar tissue from subjects with schizophrenia, bipolar disorder, and controls, from the Stanley Microarray Collection (Supplementary Table 1). We genotyped subjects for two schizophrenia-associated tag SNPs in DAO and G72/G30. We used cerebellar tissue from rats administered haloperidol or clozapine for 14 days to investigate antipsychotic effects on DAO activity. For demographic and methodological details, see Supplementary Materials. n nAs shown in Fig. 1A, DAO activity differed between groups (F2,100=4.79, p=0.010), being increased in schizophrenia compared to controls (+37%, p=0.027) and compared to bipolar disorder (+57%, p=0.004). The latter groups did not differ (p=0.45). DAO activity was not correlated with post mortem interval, brain pH, or antipsychotic exposure (Supplementary Fig. 1) or age (R=0.03, p=0.79). DAO activity was unrelated to alcohol or substance misuse history (using a five-point scale), smoking, sex, or suicide. DAO activity increased with duration of schizophrenia (R=0.34, p=0.05, n=35). Within the bipolar disorder group, DAO activity did not vary according to a history of psychotic symptoms. DAO activity correlated with DAO mRNA (R=0.43, p=0.0001, n=97). DAO affinity showed no group differences (Fig. 1B). DAO activity in rat cerebellum was unaffected by antipsychotics (Supplementary Table 2). n n n nFigure 1 n nCerebellar DAO activity and expression in 35 control subjects (CON, white bars), 35 with schizophrenia (SCZ, black bars), and 34 with bipolar disorder (BPD, shaded bars). A) DAO activity (Vmax, nmol D-proline/min/mg protein) is higher in subjects with ... n n n nNormalised DAO mRNA differed between groups (F2,88=3.84, p=0.025), being increased compared to controls in schizophrenia (p=0.01) and bipolar disorder (p=0.04; Fig. 1C). DAO mRNA was not related to antipsychotic exposure, post mortem interval, brain pH, or RIN, but was affected by death-to-refrigeration interval (Supplementary Fig. 1). n nNeither DAO activity nor DAO mRNA were influenced by the DAO or G72/G30 SNPs (Supplementary Table 3), apart from a trend for higher DAO activity in allele 2 carriers of G72/G30 rs3918342 (p=0.08 vs 1/1 homozygotes). There were no genotype-by-diagnosis interactions. n nOur data show an elevation of DAO activity in schizophrenia accompanied by increased gene expression. The activity increase confirms the results of a pilot study,5 and the elevated DAO mRNA replicates findings in a separate cohort.6 There were no correlations of DAO activity or expression with medication exposure, and no effect of haloperidol or clozapine on DAO activity in rat brain. Other confounders (e.g. smoking) did not have a demonstrable influence either. Hence, within the constraints of a post mortem study, our findings appear related to the diagnosis of schizophrenia. We focused on the cerebellum because DAO is abundant and active therein; it will be important to ascertain whether DAO activity is affected elsewhere in schizophrenia, but problematic since forebrain DAO activity is extremely low, despite robust expression. Parenthetically, this discrepancy is complemented by a difference in the cellular localization of DAO: it is glial in the cerebellum, but mainly neuronal in the cerebral cortex.6 n nElevated DAO activity will presumably enhance metabolism of D-serine and, other things being equal, contribute to a reduced synaptic availability of D-serine, potentially impairing NMDAR function.1 As such, our findings support the hypothesized involvement of DAO, and thence D-serine, in the NMDAR hypofunction of schizophrenia and its potential therapeutic amelioration.2,7,8 Clearly any such conclusions are tentative, since many other factors likely also influence D-serine availability, e.g. its synthesis by serine racemase,6,9 and its release and reuptake.10 Alterations in these processes could counteract – or exacerbate – enhanced DAO activity. Moreover, since DAO also metabolises other D-amino acids,1 D-serine is not the only substrate that might be affected by an increase in DAO activity. For example, D-alanine is present in the cerebellum, is an NMDAR modulator, and may be therapeutically beneficial in schizophrenia.7 Overall, whilst a primary effect on D-serine, and thence NMDARs, is an attractive interpretation of the DAO increase in schizophrenia, further studies are needed to confirm the biochemical consequences, as well as the causes, of the elevation. (See Supplementary Materials for further discussion). n nAs the DAO and G72/G30 SNPs did not influence DAO activity or expression, our data provide no evidence that they are functional (nor indexing SNPs that are), nor have we identified a mechanism whereby variation in these genes might confer schizophrenia susceptibility. There may be other SNPs that are relevant in this respect; alternatively, the DAO SNPs might operate at other places and times, whilst G72/G30 SNPs could act via a DAO-independent pathway. n nIn summary, DAO activity and expression are increased in schizophrenia, but not related to DAO or G72/G30 genotype. Any pathophysiological consequences of increased DAO activity seem most likely to impact on D-serine metabolism and thence NMDAR function, but this remains to be established.

How Cannabis Causes Paranoia: Using the Intravenous Administration of ∆9-Tetrahydrocannabinol (THC) to Identify Key Cognitive Mechanisms Leading to Paranoia

Paranoia is receiving increasing attention in its own right, since it is a central experience of psychotic disorders and a marker of the health of a society. Paranoia is associated with use of the most commonly taken illicit drug, cannabis. The objective was to determine whether the principal psychoactive ingredient of cannabis—∆9-tetrahydrocannabinol (THC)—causes paranoia and to use the drug as a probe to identify key cognitive mechanisms underlying paranoia. A randomized, placebo-controlled, between-groups test of the effects of intravenous THC was conducted. A total of 121 individuals with paranoid ideation were randomized to receive placebo, THC, or THC preceded by a cognitive awareness condition. Paranoia was assessed extensively via a real social situation, an immersive virtual reality experiment, and standard self-report and interviewer measures. Putative causal factors were assessed. Principal components analysis was used to create a composite paranoia score and composite causal variables to be tested in a mediation analysis. THC significantly increased paranoia, negative affect (anxiety, worry, depression, negative thoughts about the self), and a range of anomalous experiences, and reduced working memory capacity. The increase in negative affect and in anomalous experiences fully accounted for the increase in paranoia. Working memory changes did not lead to paranoia. Making participants aware of the effects of THC had little impact. In this largest study of intravenous THC, it was definitively demonstrated that the drug triggers paranoid thoughts in vulnerable individuals. The most likely mechanism of action causing paranoia was the generation of negative affect and anomalous experiences.

Decreased regional gray matter volume in S allele carriers of the 5-HTTLPR triallelic polymorphism

Decreased regional gray matter volume in S’ allele carriers of the 5-HTTLPR triallelic polymorphism

Early changes in emotional processing as a marker of clinical response to SSRI treatment in depression

Antidepressant treatment reduces behavioural and neural markers of negative emotional bias early in treatment and has been proposed as a mechanism of antidepressant drug action. Here, we provide a critical test of this hypothesis by assessing whether neural markers of early emotional processing changes predict later clinical response in depression. Thirty-five unmedicated patients with major depression took the selective serotonin re-uptake inhibitor (SSRI), escitalopram (10u2009mg), over 6 weeks, and were classified as responders (22 patients) versus non-responders (13 patients), based on at least a 50% reduction in symptoms by the end of treatment. The neural response to fearful and happy emotional facial expressions was assessed before and after 7 days of treatment using functional magnetic resonance imaging. Changes in the neural response to these facial cues after 7 days of escitalopram were compared in patients as a function of later clinical response. A sample of healthy controls was also assessed. At baseline, depressed patients showed greater activation to fear versus happy faces than controls in the insula and dorsal anterior cingulate. Depressed patients who went on to respond to the SSRI had a greater reduction in neural activity to fearful versus happy facial expressions after just 7 days of escitalopram across a network of regions including the anterior cingulate, insula, amygdala and thalamus. Mediation analysis confirmed that the direct effect of neural change on symptom response was not mediated by initial changes in depressive symptoms. These results support the hypothesis that early changes in emotional processing with antidepressant treatment are the basis of later clinical improvement. As such, early correction of negative bias may be a key mechanism of antidepressant drug action and a potentially useful predictor of therapeutic response.

Effects of the potential lithium-mimetic, ebselen, on brain neurochemistry: a magnetic resonance spectroscopy study at 7 tesla

RationaleLithium is an effective treatment for bipolar disorder, but safety issues complicate its clinical use. The antioxidant drug, ebselen, may be a possible lithium-mimetic based on its ability to inhibit inositol monophosphatase (IMPase), an action which it shares with lithium.ObjectivesOur primary aim was to determine whether ebselen lowered levels of inositol in the human brain. We also assessed the effect of ebselen on other brain neurometabolites, including glutathione, glutamate, glutamine, and glutamate + glutamine (Glx)MethodsTwenty healthy volunteers were tested on two occasions receiving either ebselen (3600xa0mg over 24xa0h) or identical placebo in a double-blind, random-order, crossover design. Two hours after the final dose of ebselen/placebo, participants underwent proton magnetic resonance spectroscopy (1H MRS) at 7 tesla (T) with voxels placed in the anterior cingulate and occipital cortex. Neurometabolite levels were calculated using an unsuppressed water signal as a reference and corrected for individual cerebrospinal fluid content in the voxel.ResultsEbselen produced no effect on neurometabolite levels in the occipital cortex. In the anterior cingulate cortex, ebselen lowered concentrations of inositol (pu2009=u20090.028, Cohen’s du2009=u20090.60) as well as those of glutathione (pu2009=u20090.033, du2009=u20090.58), glutamine (pu2009=u20090.024, du2009=u20090.62), glutamate (pu2009=u20090.01, du2009=u20090.73), and Glx (pu2009=u20090.001, du2009=u20091.0).ConclusionsThe study suggests that ebselen produces a functional inhibition of IMPase in the human brain. The effect of ebselen to lower glutamate is consistent with its reported ability to inhibit the enzyme, glutaminase. Ebselen may have potential as a repurposed treatment for bipolar disorder.

Fronto-limbic effective connectivity as possible predictor of antidepressant response to SSRI administration.

The timely selection of the optimal treatment for depressed patients is critical to improve remission rates. The detection of pre-treatment variables able to predict differential treatment response may provide novel approaches for treatment selection. Selective serotonin reuptake inhibitors (SSRIs) modulate the fronto-limbic functional response and connectivity, an effect preceding the overt clinical antidepressant effects. Here we investigated whether the cortico-limbic connectivity associated with emotional bias measured before SSRI administration predicts the efficacy of antidepressant treatment in MDD patients. fMRI and Dynamic Causal Modeling (DCM) were combined to study if effective connectivity might differentiate healthy controls (HC) and patients affected by major depression who later responded (RMDD, n=21), or failed to respond (nRMDD, n=12), to 6 weeks of escitalopram administration. Sixteen DCMs exploring connectivity between anterior cingulate cortex (ACC), ventrolateral prefrontal cortex (VLPFC), Amygdala (Amy), and fusiform gyrus (FG) were constructed. Analyses revealed that nRMDD had reduced endogenous connectivity from Amy to VLPFC and to ACC, with an increased connectivity and modulation of the ACC to Amy connectivity when processing of fearful emotional stimuli compared to HC. RMDD and HC did not significantly differ among themselves. Pre-treatment effective connectivity in fronto-limbic circuitry could be an important factor affecting antidepressant response, and highlight the mechanisms which may be involved in recovery from depression. These results suggest that fronto-limbic connectivity might provide a neural biomarker to predict the clinical outcome to SSRIs administration in major depression.

When less is more: a functional magnetic resonance imaging study of verbal working memory in remitted depressed patients.

BACKGROUNDnPatients with depression show abnormalities in the neural circuitry supporting working memory. However, it is unclear if these abnormalities are present in unmedicated remitted depressed patients. To address this question, the current study employed functional magnetic resonance imaging (fMRI), in combination with a simple verbal n-back task, in a cohort of unmedicated remitted depressed patients.nnnMETHODnWe studied 15 healthy control subjects (HC) and 15 unmedicated remitted depressed patients (rMDD). Participants performed a verbal working memory task of varying cognitive load (n-back) while undergoing fMRI. We used multiple regression analyses to assess overall capacity (1-, 2-, 3-back versus 0-back) as well as quadratic modulation of cognitive demand.nnnRESULTSnPerformance accuracy and response latency did not differ between groups, and overall capacity was similar. However, rMDD showed a positive quadratic load response in the bilateral hippocampus; the converse was true for HC.nnnCONCLUSIONSnOur data suggest that remitted depression was associated with a perturbed pattern of activation in the bilateral hippocampus during a verbal working memory task. We propose that a reduced ability to dampen task-irrelevant activity may reflect a neurobiological risk factor for recurrent depression.