Untersuchung zur Prävalenz kardialer autonomer Dysfunktion bei unmedizierten schizophrenen Patienten

Die schizophrene Erkrankung geht mit einer verkürzten Lebenserwartung von 15 bis 20 Jahren einher, die vor allem auf kardiovaskuläre Erkrankungen zurückzuführen ist. Ziel dieser Arbeit war es eine Bewertungsskala zu entwickeln, die die individuelle Ausprägung kardial autonomer Dysfunktion (CADF), als maßgeblichen Faktor für die erhöhte kardial bedingte Mortalität quantifiziert, um dann in einem weiteren Schritt zu untersuchen, wie häufig verschiedene Ausprägungen in einem großen Kollektiv unmedizierter Patienten vorkommen. Indem für jeden der 112 Patienten jeder einzelne der 13 ausgewählten Indices der Herzratenvariabilität, die aus 30-minütigen EKG-Ableitungen unter Ruhebedingungen generiert wurden, in Bezug zur ersten, eineinhalbfachen und zweiten Standardabweichung vom jeweiligen Mittelwert des gesunden Kontrollkollektivs (N=112) gesetzt wurde, wurden Bewertungspunkte vergeben, deren Gesamtpunktzahl die Zuordnung in eine der Gruppen keine, moderate und schwere CADF festlegte. Wir konnten zeigen, dass ein Drittel der Patienten von einer schwerwiegenden kardialen autonomen Dysfunktion betroffen ist, die vor allem durch erhöhte Herzfrequenzen und eine verminderte vagale Modulation charakterisiert ist. Ein Viertel zeigte keine autonomen Auffälligkeiten und die restlichen Patienten hatten moderate autonome Abweichungen. In unserer Arbeit hatten nur wenige psychopathologische und epidemiologische Indices einen geringen Einfluss auf die CADF, einen eindeutigen Zusammenhang konnten wir mit der Chronizität der schizophrenen Erkrankung zeigen. Zukünftige Untersuchungen sollten die Frage klären, wie Gesundheit und Lebensqualität der disponierten Patienten mit den moderaten und schweren kardial autonomen Veränderungen besser geschützt werden können

A common variation in HCN1 is associated with heart rate variability in schizophrenia

BackgroundThere is growing evidence for a shared genetic basis between schizophrenia risk and cardiovascular disease. Reduced efferent vagal activity, indexed by reduced heart rate variability (HRV), has been consistently described in patients with schizophrenia and may potentially contribute to the increased cardiovascular risk in these patients. In this study, we tested the hypothesis whether the established schizophrenia risk variant HCN1 rs16902086 (A > G) is associated with reduced HRV.MethodsWe analyzed the risk status of HCN1 rs16902086 (AG/GG vs. AA genotype) in 83 unmedicated patients with schizophrenia and 96 healthy controls and investigated genotype-related impacts on various HRV parameters.ResultsWe observed significantly increased resting heart rates and a marked decrease of vagal modulation in our patient cohort. Strikingly, HCN1 rs16902086 (A > G) was associated with reduced HRV parameters in patients only. A trend towards more pronounced HRV deviations was observed in homozygous (GG) compared to heterozygous patients (AG).ConclusionWe present first evidence for a genetic risk factor that is associated with decreased vagal modulation in unmedicated patients with schizophrenia. Moreover, our findings suggest that HCN1 might be involved in reduced vagal modulation and possibly in increased cardiac mortality in schizophrenia patients. Thus, our data indicate that reduced vagal modulation might be an endophenotype of schizophrenia

Analysis of CACNA1C and KCNH2 Risk Variants on Cardiac Autonomic Function in Patients with Schizophrenia

Background: Cardiac autonomic dysfunction (CADF) is a major contributor to increased cardiac mortality in schizophrenia patients. The aberrant function of voltage-gated ion channels, which are widely distributed in the brain and heart, may link schizophrenia and CADF. In search of channel-encoding genes that are associated with both CADF and schizophrenia, CACNA1C and KCNH2 are promising candidates. In this study, we tested for associations between genetic findings in both genes and CADF parameters in schizophrenia patients whose heart functions were not influenced by psychopharmaceuticals. Methods: First, we searched the literature for single-nucleotide polymorphisms (SNPs) in CACNA1C and KCNH2 that showed genome-wide significant association with schizophrenia. Subsequently, we looked for such robust associations with CADF traits at these loci. A total of 5 CACNA1C SNPs and 9 KCNH2 SNPs were found and genotyped in 77 unmedicated schizophrenia patients and 144 healthy controls. Genotype-related impacts on heart rate (HR) dynamics and QT variability indices (QTvi) were analyzed separately in patients and healthy controls. Results: We observed significantly increased QTvi in unmedicated patients with CADF-associated risk in CACNA1C rs2283274 C and schizophrenia-associated risk in rs2239061 G compared to the non-risk allele in these patients. Moreover, unmedicated patients with previously identified schizophrenia risk alleles in KCNH2 rs11763131 A, rs3807373 A, rs3800779 C, rs748693 G, and 1036145 T showed increased mean HR and QTvi as compared to non-risk alleles. Conclusions: We propose a potential pleiotropic role for common variation in CACNA1C and KCNH2 associated with CADF in schizophrenia patients, independent of antipsychotic medication, that predisposes them to cardiac arrhythmias and premature death

Cortical thickness of the posterior cingulate cortex is associated with the ketamine-induced altered sense of self: An ultra-high field MRI study

Subanesthetic doses of ketamine induce an antidepressant effect within hours in individuals with treatment-resistant depression while it furthermore induces immediate but transient psychotomimetic effects. Among these psychotomimetic effects, an altered sense of self has specifically been associated with the antidepressant response to ketamine as well as psychedelics. However, there is plenty of variation in the extent of the drug-induced altered sense of self experience that might be explained by differences in basal morphological characteristics, such as cortical thickness. Regions that have been previously associated with a psychedelics-induced sense of self and with ketamine’s mechanism of action, are the posterior cingulate cortex (PCC) and the pregenual anterior cingulate cortex (pgACC). In this randomized, placebo-controlled, double-blind cross-over magnetic resonance imaging study, thirty-five healthy male participants (mean age±standard deviation (SD)=25.1±4.2 years) were scanned at 7 T. We investigated whether the cortical thickness of two DMN regions, the PCC and the pgACC, are associated with disembodiment and experience of unity scores, which were used to index the ketamine-induced altered sense of self. We observed a negative correlation between the PCC cortical thickness and the disembodiment scores. In contrast, no significant association was found between the pgACC cortical thickness and the ketamine-induced altered sense of self. In the context of the existing literature, our findings highlight the importance of the PCC as a structure involved in the mechanism of ketamine-induced altered sense of self that seems to be shared with different antidepressant agents with psychotomimetic effects operating on different classes of transmitter systems

The effect of ketamine on affective modulation of the startle reflex and its resting-state brain correlates

Abstract Ketamine is a rapid-acting antidepressant that also influences neural reactivity to affective stimuli. However, the effect of ketamine on behavioral affective reactivity is yet to be elucidated. The affect-modulated startle reflex paradigm (AMSR) allows examining the valence-specific aspects of behavioral affective reactivity. We hypothesized that ketamine alters the modulation of the startle reflex during processing of unpleasant and pleasant stimuli and weakens the resting-state functional connectivity (rsFC) within the modulatory pathway, namely between the centromedial nucleus of the amygdala and nucleus reticularis pontis caudalis. In a randomized, double-blind, placebo-controlled, cross-over study, thirty-two healthy male participants underwent ultra-high field resting-state functional magnetic resonance imaging at 7 T before and 24 h after placebo and S-ketamine infusions. Participants completed the AMSR task at baseline and one day after each infusion. In contrast to our hypothesis, ketamine infusion did not impact startle potentiation during processing of unpleasant stimuli but resulted in diminished startle attenuation during processing of pleasant stimuli. This diminishment significantly correlated with end-of-infusion plasma levels of ketamine and norketamine. Furthermore, ketamine induced a decrease in rsFC within the modulatory startle reflex pathway. The results of this first study on the effect of ketamine on the AMSR suggest that ketamine might attenuate the motivational significance of pleasant stimuli in healthy participants one day after infusion

Association of the delayed changes in glutamate levels and functional connectivity with the immediate network effects of S-ketamine

Ketamine shows rapid antidepressant effects peaking 24 h after administration. The antidepressant effects may occur through changes in glutamatergic metabolite levels and resting-state functional connectivity (rsFC) within the default mode network (DMN). A multistage drug effect of ketamine has been suggested, inducing acute effects on dysfunctional network configuration and delayed effects on homeostatic synaptic plasticity. Whether the DMN-centered delayed antidepressant-related changes are associated with the immediate changes remains unknown. Thirty-five healthy male participants (25.1 ± 4.2 years) underwent 7 T magnetic resonance spectroscopy (MRS) and resting-state functional magnetic resonance imaging (rsfMRI) before, during, and 24 h after a single S-ketamine or placebo infusion. Changes in glutamatergic measures and rsFC in the DMN node pregenual anterior cingulate cortex (pgACC) were examined. A delayed rsFC decrease of the pgACC to inferior parietal lobe (family-wise error corrected p (pFWEc) = 0.018) and dorsolateral prefrontal cortex (PFC; pFWEc = 0.002) was detected that was preceded by an immediate rsFC increase of the pgACC to medial PFC (pFWEc < 0.001) and dorsomedial PFC (pFWEc = 0.005). Additionally, the immediate rsFC reconfigurations correlated with the delayed pgACC glutamate (Glu) level increase (p = 0.024) after 24 h at trend level (p = 0.067). Baseline measures of rsFC and MRS were furthermore associated with the magnitude of the respective delayed changes (p's < 0.05). In contrast, the delayed changes were not associated with acute psychotomimetic side effects or plasma concentrations of ketamine and its metabolites. This multimodal study suggests an association between immediate S-ketamine-induced network effects and delayed brain changes at a time point relevant in its clinical context