Lejla Colic

Temporal Dynamics of Antidepressant Ketamine Effects on Glutamine Cycling Follow Regional Fingerprints of AMPA and NMDA Receptor Densities

The anterior cingulate cortex (ACC) has shown decreased glutamate levels in patients with major depressive disorder. Subanesthetic doses of ketamine were repeatedly shown to improve depressive symptoms within 24 h after infusion and this antidepressant effect was attributed to increased α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) throughput. To elucidate ketamine’s mechanism of action, we tested whether the clinical time course of the improvement is mirrored by the change of glutamine/glutamate ratio and if such effects show a regional and temporal specificity in two distinct subdivisions of ACC with different AMPA/N-methyl-D-aspartate receptor profiles. In a double-blind, placebo-controlled intravenous infusion study of ketamine, we measured glutamate and glutamine in the pregenual ACC (pgACC) and the anterior midcingulate cortex at 1 and 24 h post infusion with magnetic resonance spectroscopy at 7 T. A significant interaction of time, region, and treatment was found for the glutamine/glutamate ratios (placebo, n=14; ketamine, n=12). Post-hoc analyses revealed that the glutamine/glutamate ratio increased significantly in the ketamine group, compared with placebo, specifically in the pgACC after 24 h. The glutamine/glutamate increase in the pgACC caused by ketamine at 24 h post infusion was reproduced in an enlarged sample (placebo, n=24; ketamine, n=20). Our results support a significant temporal and regional response in glutamine/glutamate ratios to a single subanesthetic dose of ketamine, which mirrors the time course of the antidepressant response and reversal of the molecular deficits in patients and which may be associated with the histoarchitectonical receptor fingerprints of the ACC subregions.

Factors Influencing the Cardiovascular Response to Subanesthetic Ketamine: A Randomized, Placebo-Controlled Trial

Abstract Background The increasing use of ketamine as a potential rapid-onset antidepressant necessitates a better understanding of its effects on blood pressure and heart rate, well-known side effects at higher doses. For the subanesthetic dose used for depression, potential predictors of these cardiovascular effects are important factors influencing clinical decisions. Since ketamine influences the sympathetic nervous system, we investigated the impact of autonomic nervous system-related factors on the cardiovascular response: a genetic polymorphism in the norepinephrine transporter and gender effects. Methods Blood pressure and heart rate were monitored during and following administration of a subanesthetic dose of ketamine or placebo in 68 healthy participants (mean age 26.04 ±5.562 years) in a double-blind, randomized, controlled, parallel-design trial. The influences of baseline blood pressure/heart rate, gender, and of a polymorphism in the norepinephrine transporter gene (NET SLC6A2, rs28386840 [A-3081T]) on blood pressure and heart rate changes were investigated. To quantify changes in blood pressure and heart rate, we calculated the maximum change from baseline (ΔMAX) and the time until maximum change (TΔMAX). Results Systolic and diastolic blood pressure as well as heart rate increased significantly upon ketamine administration, but without reaching hypertensive levels. During administration, the systolic blood pressure at baseline (TP0Sys) correlated negatively with the time to achieve maximal systolic blood pressure (TΔMAXSys, P<.001). Furthermore, women showed higher maximal diastolic blood pressure change (ΔMAXDia, P<.001) and reached this peak earlier than men (TΔMAXDia, P=.017) at administration. NET rs28386840 [T] carriers reached their maximal systolic blood pressure during ketamine administration significantly earlier than [A] homozygous (TΔMAXSys, P=.030). In a combined regression model, both genetic polymorphism and TP0Sys were significant predictors of TΔMAXSys (P<.0005). Conclusions Subanesthetic ketamine increased both blood pressure and heart rate without causing hypertensive events. Furthermore, we identified gender and NET rs28386840 genotype as factors that predict increased cardiovascular sequelae of ketamine administration in our young, healthy study population providing a potential basis for establishing monitoring guidelines.

Metabolic mapping reveals sex dependent involvement of default mode and salience network in alexithymia

Alexithymia, a personality construct marked by difficulties in processing ones emotions, has been linked to the altered activity in the anterior cingulate cortex (ACC). Although longitudinal studies reported sex differences in alexithymia, what mediates them is not known. To investigate sex-specific associations of alexithymia and neuronal markers, we mapped metabolites in four brain regions involved differentially in emotion processing using a point-resolved spectroscopy MRS sequence in 3 Tesla. Both sexes showed negative correlations between alexithymia and N-acetylaspartate (NAA) in pregenual ACC (pgACC). Women showed a robust negative correlation of the joint measure of glutamate and glutamine (Glx) to NAA in posterior cingulate cortex (PCC), whereas men showed a weak positive association of Glx to NAA in dorsal ACC (dACC). Our results suggest that lowered neuronal integrity in pgACC, a region of the default mode network (DMN), might primarily account for the general difficulties in emotional processing in alexithymia. Association of alexithymia in women extends to another region in the DMN-PCC, while in men a region in the salience network (SN) was involved. These observations could be representative of sex specific regulation strategies that include diminished internal evaluation of feelings in women and cognitive emotion suppression in men.

Functional connectivity changes following interpersonal reactivity

Attachment experiences substantially influence emotional and cognitive development. Narratives comprising attachment‐dependent content were proposed to modulate activation of cognitive‐emotional schemata in listeners. We studied the effects after listening to prototypical attachment narratives on wellbeing and countertransference‐reactions in 149 healthy participants. Neural correlates of these cognitive‐emotional schema activations were investigated in a 7 Tesla rest‐task‐rest fMRI‐study (23 healthy males) using functional connectivity (FC) analysis of the social approach network (seed regions: left and right Caudate Nucleus, CN). Reduced FC between left CN and bilateral dorsolateral prefrontal cortex (DLPFC) represented a general effect of prior auditory stimulation. After presentation of the insecure‐dismissing narrative, FC between left CN and bilateral temporo‐parietal junction, and right dorsal posterior Cingulum was reduced, compared to baseline. Post‐narrative FC‐patterns of insecure‐dismissing and insecure‐preoccupied narratives differed in strength between left CN and right DLPFC. Neural correlates of the moderating effect of individual attachment anxiety were represented in a reduced CN‐DLPFC FC as a function of individual neediness‐levels. These findings suggest specific neural processing of prolonged mood‐changes and schema activation induced by attachment‐specific speech patterns. Individual desire for interpersonal proximity was predicted by attachment anxiety and furthermore modulated FC of the social approach network in those exposed to such narratives.

Increased levels of 5HT2A receptor mRNA expression in peripheral blood mononuclear cells of patients with major depression: correlations with severity and duration of illness.

Abstract Background: Neuroimaging, immunologic, and pharmacologic studies have emphasized the role of 5-HT2A and 5-HT3A serotonin receptors in the pathophysiology of major depression. Aim: The aim of this study was to measure the relative expression of 5-HT2A and 5-HT3A receptor mRNA in peripheral blood mononuclear cells (PBMCs) of patients with major depressive disorder (MDD). Method: 5-HT2A and 5-HT3A receptor mRNA expressions were examined in PBMCs of 25 medication-naïve-patients with MDD, 25 medication-free MDD patients, and 25 healthy controls. 5-HT2A and 5-HT3A receptor mRNA expressions were measured using real-time quantitative PCR. This study evaluated patients’ clinical symptoms using the Hamilton Depression Rating Scale-17 items (HDRS) and the Beck Depression Inventory (BDI). Results: Relative 5-HTR2A mRNA expression was significantly higher in PBMCs of all MDD patients when compared with healthy controls (Z = −3.875, p < 0.05). However, there was no significant difference in the relative levels of 5-HTR3A mRNA expression in PBMCs of all MDD patients when compared with healthy controls (Z = −1.328, p > 0.05). MDD patients showed significant correlations between 5-HTR2A mRNA expression and HDRS scores (rs = 0.902, p < 0.001) and BDI scores (rs = 0.878, p < 0.001). Conclusion: This study showed that depressed patients, irrespective of treatment, have higher 5-HTR2A mRNA levels in PBMCs than healthy subjects. It also provided evidence that 5-HTR2A mRNA levels in PBMCs of MDD patients could be associated with the severity of depression and the duration of the illness.

GAD65 promoter polymorphism rs2236418 modulates harm avoidance in women via inhibition/excitation balance in the rostral ACC

Anxiety disorders are common and debilitating conditions with higher prevalence in women. However, factors that predispose women to anxiety phenotypes are not clarified. Here we investigated potential contribution of the single nucleotide polymorphism rs2236418 in GAD2 gene to changes in regional inhibition/excitation balance, anxiety-like traits, and related neural activity in both sexes. One hundred and five healthy individuals were examined with high-field (7T) multimodal magnetic resonance imaging (MRI); including resting-state functional MRI in combination with assessment of GABA and glutamate (Glu) levels via MR spectroscopy. Regional GABA/Glu levels in anterior cingulate cortex (ACC) subregions were assessed as mediators of gene–personality interaction for the trait harm avoidance and moderation by sex was tested. In AA homozygotes, with putatively lower GAD2 promoter activity, we observed increased intrinsic neuronal activity and higher inhibition/excitation balance in pregenual ACC (pgACC) compared with G carriers. The pgACC drove a significant interaction of genotype, region, and sex, where inhibition/excitation balance was significantly reduced only in female AA carriers. This finding was specific for rs2236418 as other investigated single nucleotide polymorphisms of the GABA synthesis related enzymes (GAD1, GAD2, and GLS) were not significant. Furthermore, only in women there was a negative association of pgACC GABA/Glu ratios with harm avoidance. A moderated-mediation model revealed that pgACC GABA/Glu also mediated the association between the genotype variant and level of harm avoidance, dependent on sex. Our data thus provide new insights into the neurochemical mechanisms that control emotional endophenotypes in humans and constitute predisposing factors for the development of anxiety disorders in women. SIGNIFICANCE STATEMENT Anxiety disorders are among the most common and burdensome psychiatric disorders, with higher prevalence rates in women. The causal mechanisms are, however, poorly understood. In this study we propose a neurobiological basis that could help to explain female bias of anxiety endophenotypes. Using magnetic resonance brain imaging and personality questionnaires we show an interaction of the genetic variation rs2236418 in the GAD2 gene and sex on GABA/glutamate (Glu) balance in the pregenual anterior cingulate cortex (pgACC), a region previously connected to affect regulation and anxiety disorders. The GAD2 gene polymorphism further influenced baseline neuronal activity in the pgACC. Importantly, GABA/Glu was shown to mediate the relationship between the genetic variant and harm avoidance, however, only in women.

Complex Role of the Serotonin Receptors in Depression: Implications for Treatment

Evidence from pharmacological, neuroimaging, postmortem, and genetic studies underlines the various roles of 5-HT receptor subtypes in the pathogenesis of major depressive disorder. Recent investigations further supported the notion of their interaction with the antidepressant medication and advanced the knowledge on underlying mechanisms of their action. The heterogeneous properties of individual 5-HT receptors offer a chance for development of new generation of antidepressants, which may be more beneficial and effective than traditional selective serotonin reuptake inhibitors (SSRIs). Antagonists of 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors, as well as agonists of 5-HT1A, 5-HT1B, 5-HT2C, 5-HT4, and 5-HT6 receptors, were observed to produce antidepressant-like responses. Paradoxical antidepressant-like effects of both agonists and antagonists of 5-HT receptors are likely connected to the diverse neurochemical mechanisms they instantiate. Augmented behavioral effects of SSRIs and other antidepressants used in combined treatment with 5-HT receptor agonists or antagonists have also been reported. The involvement of 5-HT receptors in depression is complex. Identifying the role of 5-HT receptors in response to antidepressants is an essential step in recognizing their mechanisms of action and, thereby, potentially producing more effective antidepressants with fewer side effects in patients with major depressive disorder.

Ketamine influences the locus coeruleus norepinephrine network, with a dependency on norepinephrine transporter genotype – a placebo controlled fMRI study

Background Ketamine is receiving increasing attention as a rapid-onset antidepressant in patients suffering from major depressive disorder (MDD) with treatment resistance or severe suicidal ideation. Ketamine modulates several neurotransmitter systems, including norepinephrine via the norepinephrine transporter (NET), both peripherally and centrally. The locus coeruleus (LC), which has high NET concentration, has been attributed to brain networks involved in depression. Thus we investigated the effects of single-dose of racemic ketamine on the LC using resting state functional MRI. Methods Fifty-nine healthy participants (mean age 25.57 ± 4.72) were examined in a double-blind, randomized, placebo-controlled study with 7 Tesla MRI. We investigated the resting state functional connectivity (rs-fc) of the LC before and one hour after subanesthetic ketamine injection (0.5 mg/kg), as well as associations between its rs-fc and a common polymorphism in the NET gene (rs28386840). Results A significant interaction of drug and time was revealed, and post hoc testing showed decreased rs-fc between LC and the thalamus after ketamine administration compared with baseline levels, including the mediodorsal, ventral anterior, ventral lateral, ventral posterolateral and centromedian nuclei. The rs-fc reduction was more pronounced in NET rs28386840 [AA] homozygous subjects than in [T] carriers. Conclusions We demonstrated acute rs-fc changes after ketamine administration in the central node of the norepinephrine pathway. These findings may contribute to understanding the antidepressant effect of ketamine at the system level, supporting modes of action on networks subserving aberrant arousal regulation in depression.

Pedophilic sex offenders are characterised by reduced GABA concentration in dorsal anterior cingulate cortex

A pedophilic disorder is characterised by abnormal sexual urges towards prepubescent children. Child abusive behavior is frequently a result of lack of behavioral inhibition and current treatment options entail, next to suppressing unchangeable sexual orientation, measures to increase cognitive and attentional control. We tested, if in brain regions subserving attentional control of behavior and perception of salient stimuli, such inhibition deficit can be observed also on the level of inhibitory neurotransmitters. We measured GABA concentration in the dorsal anterior cingulate cortex (dACC) and in a control region, the pregenual anterior cingulate cortex (pgACC) in pedophilic sex offenders (N = 13) and matched controls (N = 13) using a 7 Tesla STEAM magnetic resonance spectroscopy (MRS). In dACC but not in the control region pedophilic sex offenders showed reduced GABA/Cr concentrations compared to healthy controls. The reduction was robust after controlling for potential influence of age and gray matter proportion within the MRS voxel (p < 0.04). Importantly, reduced GABA/Cr in patients was correlated with lower self-control measured with the Barratt Impulsiveness Scale (p = 0.028, r = −0.689). In a region related to cognitive control and salience mapping, pedophilic sex offenders showed reduction of the inhibitory neurotransmitter GABA which may be seen as a neuronal correlate of inhibition and behavioral control.

Effects of natural medicinal on brain responses to deviant stimuli during an auditory oddball task

Abstracts of the WASAD Conference 2017, 14–16 September, Würzburg, Germanys of the WASAD Conference 2017, 14–16 September, Würzburg, Germany