Using Heart Rate Variability to Assess Nurses' Stress During the COVID-19 Pandemic.

OBJECTIVE: This study aimed to assess subjective and objective parameters of stress among nurses during the COVID-19 pandemic and to examine the recovery effect of a day off. METHODS: In this prospective observational trial, we measured heart rate variability (using a wearable device) and perceived stress levels on 3 working days and 1 day off. We obtained the following data using an online questionnaire: working conditions, COVID-19-related problems, depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder-7), effort-reward imbalance, and work-family conflict in a sample of German nurses (N = 41). RESULTS: When comparing working days with a day off, we observed a significant difference for physical load (Cohen's d = 0.798, P < .001), mental load (Cohen's d = 0.660, P = .001), emotional exhaustion (Cohen's d = 0.945, P < .001), and overburdening (Cohen's d = 0.585, P = .002) with higher scores on working days. Regarding heart rate variability, we did not find a difference. Correlational analyses revealed a significant association between being afraid to get infected with COVID-19 and lower heart rate variability (r = -0.336, P = .045) and between being afraid to infect relatives and lower heart rate variability (r = -0.442, P = .007). Furthermore, a higher total sum score of work-family conflict was significantly associated with lower heart rate variability (r = -0.424, P = .01). CONCLUSION: As heart rate variability observations were different from those regarding subjectively perceived stress, further studies are needed to evaluate and differentiate the influence of work stress and other types of stress on heart rate variability.

Exacerbation of central serous chorioretinopathy during trauma-confronting psychotherapy- a case report.

BACKGROUND: Psychotherapy for post-traumatic stress disorder, in particular trauma-confronting psychotherapy, can be associated with increased stress. However, research on the somatic impact and psychosomatic interactions of these psychological stress reactions is lacking. We report on a 43-year old man whose central serous chorioretinopathy exacerbated upon trauma-confronting psychotherapy. CASE PRESENTATION: We report on a man with pre-diagnosed, asymptomatic central serous chorioretinopathy who underwent inpatient psychosomatic therapy. He disclosed a history of sexual abuse by a family member and consequently showed intrusions, flashbacks, nightmares, avoidance behavior, and hyperarousal. Thus, we diagnosed post-traumatic stress disorder. After a stabilization phase, he underwent trauma-focused psychotherapy including trauma confrontation. In the course of this treatment, acute vision loss with blurred vision and image distortion of his right eye occurred. An ophthalmologic visit confirmed a relapse of a pre-diagnosed central serous chorioretinopathy. The analysis of stress biomarkers showed a decrease in testosterone levels and a noon peak in diurnal cortisol secretion, which is indicative of a stress reaction. CONCLUSION: Central serous chorioretinopathy may exacerbate upon psychotherapeutic treatment. In this case, an exacerbation of chorioretinopathy was observed in direct relation to the therapeutic intervention. Psychotherapists and ophthalmologists should collaborate in the psychotherapeutic treatment of patients with chorioretinopathy. Our case demonstrates the need to consider the possible increased stress levels during psychotherapy and resulting physical side effects, such as exacerbation of an existing condition. It is advisable to adjust the level of generated stress particularly well in the presence of stress-inducible physical diseases. Our case is a good example of the interplay between psychological and physical stress.

Paradoxical effect of anti-inflammatory drugs on IL-6 mRNA expression in patients with PTSD during treatment.

The pathophysiology of posttraumatic stress disorder (PTSD) is associated with the activation of the innate immune system, including cytokines like interleukin 6 (IL-6). However, the role of IL-6 in the etiology and treatment of PTSD still remains elusive. We conducted a prospective controlled trial to investigate the development of IL-6 during psychosomatic treatment in individuals with PTSD in comparison with individuals without PTSD. We assessed IL-6 mRNA expression before and after 2 months of psychosomatic treatment in individuals with and without PTSD. Severities of PTSD and depressive symptoms were assessed in parallel. Linear mixed regression was applied for statistical analysis, including the factors diagnosis PTSD and pre-post treatment after subgrouping for intake of anti-inflammatory drugs. The development of IL-6 mRNA expression during treatment was affected by the use of anti-inflammatory drugs. In the subgroup without intake of anti-inflammatory drugs, no significant statistical treatment effect in individuals with and without PTSD emerged. In the subgroup of individuals taking anti-inflammatory drugs, a significant interaction effect of the factors pre-post treatment and diagnosis PTSD was observed. Whereas IL-6 mRNA expression in individuals without PTSD decreased according to amelioration of symptoms, IL-6 mRNA expression in individuals with PTSD increased significantly during treatment, in opposite direction to symptom severity. Anti-inflammatory drugs might affect IL-6 mRNA expression in individuals with PTSD in a paradoxical way. This study offers a further piece of evidence that IL-6 could be involved in the pathophysiology of PTSD and PTSD-specific immunologic molecular mechanisms.

Acute stress responses of autonomous nervous system, HPA axis, and inflammatory system in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) does not only have direct consequences for well-being, but it also comes with a significant risk for severe somatic health consequences. A number of previous studies have pointed to alterations in stress systems in traumatized persons, as well as the inflammatory system, which might be important links in the pathway between trauma, PTSD, and health consequences. The aim of this study was to investigate acute stress responses in PTSD patients compared with healthy controls. Twenty-seven PTSD patients and 15 controls were exposed to the Trier Social Stress Test (TSST), and we measured salivary cortisol, salivary alpha-amylase (sAA), plasma interleukin-6 (IL-6), as well as heart rate and heart rate variability (HRV) at different time points before, during and after the stress test. Results revealed similar stress responses between patients and controls, but lower baseline cortisol levels and higher IL-6 baseline levels in PTSD patients. Increases in sAA stress responses were significantly lower in patients, while sAA concentrations were higher in the PTSD group during intervention. HRV was markedly decreased in patients and showed a significantly blunted acute stress response with a slower recovery after TSST. These results confirm previous findings of marked stress system dysregulations in PTSD and add to the literature on acute stress reactivity in PTSD which appears to show stress system-specific changes. Overall, these results have implications for our understanding of potential risk and resilience factors in the response to trauma.

Adult alcohol drinking and emotional tone are mediated by neutral sphingomyelinase during development in males.

Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior.

Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects.

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone-brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental-physical co-morbidity trias of alcohol abuse-depression/anxiety-bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental-physical co-morbidity trias.

Synthesis and characterization of a new two photon excitable acid sphingomyelinase FRET probe.

Recently, FRET probes for acid sphingomyelinase (ASM) have enabled the observation of enzyme activity in intact cells for the first time. Here we present an ASM FRET probe specifically optimized for 2-photon excitation. To facilitate probe characterization and comparison to the previous probe, we mixed the two intact probes with defined amounts of the probes' ceramide cleavage products and mounted them on lipid beads. Directly excited NBD FRET acceptor fluorescene proved to be a useful means of reference and showed that the new probe is brighter, albeit only moderately, than the previous one. The new probe was then used to detect inhibition by various ASM inhibitors microscopically for the first time. Also in cells, directly excited acceptor fluorescence proved to be a useful parameter in addition to FRET to visualize inhibition of ASM.

mRNA Expression of SMPD1 Encoding Acid Sphingomyelinase Decreases upon Antidepressant Treatment.

Major depressive disorder (MDD) is a severe psychiatric condition with key symptoms of low mood and lack of motivation, joy, and pleasure. Recently, the acid sphingomyelinase (ASM)/ceramide system has been implicated in the pathogenesis of MDD. ASM is a lysosomal glycoprotein that catalyzes the hydrolysis of sphingomyelin, an abundant component of membranes, into the bioactive sphingolipid ceramide, which impacts signaling pathways. ASM activity is inhibited by several common antidepressant drugs. Human and murine studies have confirmed that increased ASM activity and ceramide levels are correlated with MDD. To define a molecular marker for treatment monitoring, we investigated the mRNA expression of SMPD1, which encodes ASM, in primary cell culture models, a mouse study, and a human study with untreated MDD patients before and after antidepressive treatment. Our cell culture study showed that a common antidepressant inhibited ASM activity at the enzymatic level and also at the transcriptional level. In a genetically modified mouse line with depressive-like behavior, Smpd1 mRNA expression in dorsal hippocampal tissue was significantly decreased after treatment with a common antidepressant. The large human study showed that SMPD1 mRNA expression in untreated MDD patients decreased significantly after antidepressive treatment. This translational study shows that SMPD1 mRNA expression could serve as a molecular marker for treatment and adherence monitoring of MDD.

Interleukin-6 secretion upon acute psychosocial stress as a potential predictor of psychotherapy outcome in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a severe mental disorder that can develop after a traumatic event. PTSD has been reported to be associated with activation of the innate immune system, as measured by increased levels of pro-inflammatory cytokines. While it is well known that PTSD patients display increased levels of interleukin 6 (IL-6) when compared with healthy controls, the relationship between cytokine secretion and treatment outcome has been hardly investigated yet. The aim of this study was to assess the potential association of inflammatory activation and therapy outcome in PTSD. Before therapeutic intervention, we applied the Trier Social Stress Test (TSST) as a method to elicit psychosocial stress and an acute inflammatory response. IL-6 levels were measured in blood plasma of PTSD patients at different time points before and after the TSST. Severity of depressive, trauma-related, and somatic symptoms was assessed before and 8 weeks after trauma-focused treatment in a multimodal day clinic setting. We showed that high reactivity of IL-6 to psychosocial stress at the beginning of the therapy was associated with a negative therapy outcome in PTSD, especially regarding depressive symptoms. This study suggests plasma IL-6 reactivity as a potential molecular marker to predict treatment outcome in PTSD.

Acid Sphingomyelinase Impacts Canonical Transient Receptor Potential Channels 6 (TRPC6) Activity in Primary Neuronal Systems.

: The acid sphingomyelinase (ASM)/ceramide system exhibits a crucial role in the pathology of major depressive disorder (MDD). ASM hydrolyzes the abundant membrane lipid sphingomyelin to ceramide that regulates the clustering of membrane proteins via microdomain and lipid raft organization. Several commonly used antidepressants, such as fluoxetine, rely on the functional inhibition of ASM in terms of their antidepressive pharmacological effects. Transient receptor potential canonical 6 (TRPC6) ion channels are located in the plasma membrane of neurons and serve as receptors for hyperforin, a phytochemical constituent of the antidepressive herbal remedy St. John's wort. TRPC6 channels are involved in the regulation of neuronal plasticity, which likely contributes to their antidepressant effect. In this work, we investigated the impact of reduced ASM activity on the TRPC6 function in neurons. A lipidomic analysis of cortical brain tissue of ASM deficient mice revealed a decrease in ceramide/sphingomyelin molar ratio and an increase in sphingosine. In neurons with ASM deletion, hyperforin-mediated Ca2+-influx via TRPC6 was decreased. Consequently, downstream activation of nuclear phospho-cAMP response element-binding protein (pCREB) was changed, a transcriptional factor involved in neuronal plasticity. Our study underlines the importance of balanced ASM activity, as well as sphingolipidome composition for optimal TRPC6 function. A better understanding of the interaction of the ASM/ceramide and TRPC6 systems could help to draw conclusions about the pathology of MDD.

Association of a CAMK2A genetic variant with logical memory performance and hippocampal volume in the elderly.

Calcium/Calmodulin-dependent kinase alpha (αCaMKII) has been shown to play an essential role in synaptic plasticity and in learning and memory in animal models. However, there is little evidence for an involvement in specific memories in humans. Here we tested the potential involvement of the αCaMKII coding gene CAMK2A in verbal logical memory in two Caucasian populations from Germany, in a sample of 209 elderly people with cognitive impairments and a sample of 142 healthy adults. The association of single nucleotide polymorphisms (SNPs) located within the genomic region of CAMK2A with verbal logical memory learning and retrieval from the Wechsler Memory Scale was measured and hippocampal volume was assessed by structural MRI. In the elderly people, we found the minor allele of CAMK2A intronic SNP rs919741 to predict a higher hippocampal volume and better logical memory retrieval. This association was not found in healthy adults. The present study may provide evidence for an association of a genetic variant of the CAMK2A gene specifically with retrieval of logical memory in elderly humans. This effect is possibly mediated by a higher hippocampal volume.

The Forebrain-Specific Overexpression of Acid Sphingomyelinase Induces Depressive-Like Symptoms in Mice.

Human and murine studies identified the lysosomal enzyme acid sphingomyelinase (ASM) as a target for antidepressant therapy and revealed its role in the pathophysiology of major depression. In this study, we generated a mouse model with overexpression of Asm (Asm-tgfb) that is restricted to the forebrain to rule out any systemic effects of Asm overexpression on depressive-like symptoms. The increase in Asm activity was higher in male Asm-tgfb mice than in female Asm-tgfb mice due to the breeding strategy, which allows for the generation of wild-type littermates as appropriate controls. Asm overexpression in the forebrain of male mice resulted in a depressive-like phenotype, whereas in female mice, Asm overexpression resulted in a social anxiogenic-like phenotype. Ceramides in male Asm-tgfb mice were elevated specifically in the dorsal hippocampus. mRNA expression analyses indicated that the increase in Asm activity affected other ceramide-generating pathways, which might help to balance ceramide levels in cortical brain regions. This forebrain-specific mouse model offers a novel tool for dissecting the molecular mechanisms that play a role in the pathophysiology of major depression.

Acid sphingomyelinase - a regulator of canonical transient receptor potential channel 6 (TRPC6) activity.

Recent investigations propose the acid sphingomyelinase (ASM)/ceramide system as a novel target for antidepressant action. ASM catalyzes the breakdown of the abundant membrane lipid sphingomyelin to the lipid messenger ceramide. This ASM-induced lipid modification induces a local shift in membrane properties, which influences receptor clustering and downstream signaling. Canonical transient receptor potential channels 6 (TRPC6) are non-selective cation channels located in the cell membrane that play an important role in dendritic growth, synaptic plasticity and cognition in the brain. They can be activated by hyperforin, an ingredient of the herbal remedy St. John's wort for treatment of depression disorders. Because of their role in the context of major depression, we investigated the crosstalk between the ASM/ceramide system and TRPC6 ion channels in a pheochromocytoma cell line 12 neuronal cell model (PC12 rat pheochromocytoma cell line). Ca2+ imaging experiments indicated that hyperforin-induced Ca2+ influx through TRPC6 channels is modulated by ASM activity. While antidepressants, known as functional inhibitors of ASM activity, reduced TRPC6-mediated Ca2+ influx, extracellular application of bacterial sphingomyelinase rebalanced TRPC6 activity in a concentration-related way. This effect was confirmed in whole-cell patch clamp electrophysiology recordings. Lipidomic analyses revealed a decrease in very long chain ceramide/sphingomyelin molar ratio after ASM inhibition, which was connected with changes in the abundance of TRPC6 channels in flotillin-1-positive lipid rafts as visualized by western blotting. Our data provide evidence that the ASM/ceramide system regulates TRPC6 channels likely by controlling their recruitment to specific lipid subdomains and thereby fine-tuning their physical properties.

Alpha-Synuclein RNA Expression is Increased in Major Depression.

Alpha-synuclein (SNCA) is a small membrane protein that plays an important role in neuro-psychiatric diseases. It is best known for its abnormal subcellular aggregation in Lewy bodies that serves as a hallmark of Parkinson's disease (PD). Due to the high comorbidity of PD with depression, we investigated the role of SNCA in patients suffering from major depressive disorder (MDD). SNCA mRNA expression levels were analyzed in peripheral blood cells of MDD patients and a healthy control group. SNCA mRNA expression was positively correlated with severity of depression as indicated by psychometric assessment. We found a significant increase in SNCA mRNA expression levels in severely depressed patients compared with controls. Thus, SNCA analysis could be a helpful target in the search for biomarkers of MDD.

Immunoregulatory role of acid sphingomyelinase in allergic asthma.

Acid sphingomyelinase (ASM) is one of the enzymes that catalyzes the breakdown of sphingomyelin to ceramide and phosphorylcholine. In this study, we aimed at elucidating the role of ASM in allergic asthma. We used an ovalbumin-induced murine model of asthma where we compared wild-type and ASM-deficient mice. In wild-type mice, secretory ASM activity in the bronchoalveolar lavage fluid was increased in the acute ovalbumin model, but not in a tolerogenic model. Furthermore, in the absence of ASM, the serum IgE level was reduced, compared with wild-type mice, while an accumulation of interstitial macrophages and foreign antigen-induced regulatory T cells along with exhausted CD4+ PD1+ T cells was observed in the lungs of ASM-/- mice. In conclusion, in the absence of ASM, we observed an accumulation of immunosuppressive antigen-induced regulatory T cells expressing Foxp3 and CTLA4 in the lung as well as multinucleated interstitial macrophages and exhausted CD4+ PD1+ T cells associated with inhibition of serum IgE in asthma.

Chronic Psychosocial Stress in Mice Is Associated With Increased Acid Sphingomyelinase Activity in Liver and Serum and With Hepatic C16:0-Ceramide Accumulation.

Chronic psychosocial stress adversely affects human morbidity and is a risk factor for inflammatory disorders, liver diseases, obesity, metabolic syndrome, and major depressive disorder (MDD). In recent studies, we found an association of MDD with an increase of acid sphingomyelinase (ASM) activity. Thus, we asked whether chronic psychosocial stress as a detrimental factor contributing to the emergence of MDD would also affect ASM activity and sphingolipid (SL) metabolism. To induce chronic psychosocial stress in male mice we employed the chronic subordinate colony housing (CSC) paradigm and compared them to non-stressed single housed control (SHC) mice. We determined Asm activity in liver and serum, hepatic SL concentrations as well as hepatic mRNA expression of genes involved in SL metabolism. We found that hepatic Asm activity was increased by 28% (P = 0.006) and secretory Asm activity by 47% (P = 0.002) in stressed mice. C16:0-Cer was increased by 40% (P = 0.008). Gene expression analysis further revealed an increased expression of tumor necrosis factor (TNF)-α (P = 0.009) and of several genes involved in SL metabolism (Cers5, P = 0.028; Cers6, P = 0.045; Gba, P = 0.049; Gba2, P = 0.030; Ormdl2, P = 0.034; Smpdl3B; P = 0.013). Our data thus provides first evidence that chronic psychosocial stress, at least in mice, induces alterations in SL metabolism, which in turn might be involved in mediating the adverse health effects of chronic psychosocial stress and peripheral changes occurring in mood disorders.

FRET probes for measuring sphingolipid metabolizing enzyme activity.

Förster resonance energy transfer (FRET) probes are unique tools in biology, as they allow for a non-destructive monitoring of a certain state of a biomolecule or of an artificial substrate within living cells in real time. FRET substrates indicate their relative cleavage rate and thus the in situ activity of a given enzyme. In contrast to quenched probes or turn-on probes, one of the two separate signals of the FRET probes can be used as internal reference, which makes ratio-imaging and quantitation of cleavage events independent of cellular delivery possible. In this review, we describe the first examples of sphingolipid FRET probes in comparison to different alternative probes. Finally, we give an outlook on future probes and their potential application.

Derivatization of common antidepressant drugs increases inhibition of acid sphingomyelinase and reduces induction of phospholipidosis.

In recent studies, major depressive disorder (MDD) was linked to an increase in acid sphingomyelinase (ASM) activity. Several drugs that are commonly used to treat MDD functionally inhibit the lysosomal enzyme ASM and are called functional inhibitors of ASM (FIASMAs). These drugs are classified as cationic amphiphilic drugs (CADs) that influence the catalytic activities of different lysosomal enzymes. This action results in the side effect of phospholipidosis (PLD), which describes a detrimental increase in the phospholipid content in lysosomes. FIASMAs differ only slightly in their physico-chemical properties, but their effects on ASM activity and induction of the lysosomal phospholipid content vary significantly. In this study, we systematically induced minor chemical modifications to the FIASMAs imipramine, desipramine and fluoxetine. We generated a library of 45 new CADs with slightly different log P (logarithmic partition coefficient) and pKa (logarithmic acid dissociation constant) values. The effects of the compounds on the ASM activity and lysosomal phospholipid content were assessed in cell culture assays. We identified four compounds with beneficial effects, i.e., increased ASM activity inhibition and reduced PLD induction compared with the original drugs. The compounds HT04, RH272B and RH272D outperformed the original imipramine, whereas RH281A performed better than desipramine. Thus, minor chemical variations of CADs impact lysosomal metabolism in a specific manner and can lead to antidepressant drugs with less deleterious side effects.

Identification of an acid sphingomyelinase ceramide kinase pathway in the regulation of the chemokine CCL5.

Acid sphingomyelinase (ASM) hydrolyzes sphingomyelin to produce the biologically active lipid ceramide. Previous studies have implicated ASM in the induction of the chemokine CCL5 in response to TNF-α however, the lipid mediator of this effect was not established. In the present study, we identified a novel pathway connecting ASM and ceramide kinase (CERK). The results show that TNF-α induces the formation of ceramide 1-phosphate (C-1-P) in a CERK-dependent manner. Silencing of CERK blocks CCL5 production in response to TNF-α. Interestingly, cells lacking ASM have decreased C-1-P production following TNF-α treatment, suggesting that ASM may be acting upstream of CERK. Functionally, ASM and CERK induce a highly concordant program of cytokine production and both are required for migration of breast cancer cells. Taken together, these data suggest ASM can produce ceramide which is then converted to C-1-P by CERK, and that C-1-P is required for production of CCL5 and several cytokines and chemokines, with roles in cell migration. These results highlight the diversity in action of ASM through more than one bioactive sphingolipid.

Additive sex-specific influence of common non-synonymous DISC1 variants on amygdala, basal ganglia, and white cortical surface area in healthy young adults.

The disrupted-in-schizophrenia-1 (DISC1) gene is known for its role in the development of mental disorders. It is also involved in neurodevelopment, cognition, and memory. To investigate the association between DISC1 variants and brain morphology, we analyzed the influence of the three common non-synonymous polymorphisms in DISC1 on specific brain structures in healthy young adults. The volumes of brain regions were determined in 145 subjects by magnetic resonance imaging and automated analysis using FreeSurfer. Genotyping was performed by high resolution melting of amplified products. In an additive genetic model, rs6675281 (Leu607Phe), rs3738401 (Arg264Gln), and rs821616 (Ser704Cys) significantly explained the volume variance of the amygdala (p = 0.007) and the pallidum (p = 0.004). A higher cumulative portion of minor alleles was associated with larger volumes of the amygdala (p = 0.005), the pallidum (p = 0.001), the caudate (p = 0.024), and the putamen (p = 0.007). Sex-stratified analysis revealed a strong genetic effect of rs6675281 on putamen and pallidum in females but not in males and an opposite influence of rs3738401 on the white cortical surface in females compared to males. The strongest single association was found for rs821616 and the amygdala volume in male subjects (p < 0.001). No effect was detected for the nucleus accumbens. We report-to our knowledge-for the first time a significant and sex-specific influence of common DISC1 variants on volumes of the basal ganglia, the amygdala and on the cortical surface area. Our results demonstrate that the additive model of all three polymorphisms outperforms their single analysis.