Alexander Kautzky

Sex-specific-differences in cardiometabolic risk in type 1 diabetes: a cross-sectional study

BackgroundLittle is known about the impact of sex-specific differences in the management of type 1 diabetes (T1DM).Thus, we evaluated the influence of gender on risk factors, complications, clinical care and adherence in patients with T1DM.MethodsIn a cross-sectional study, sex-specific disparities in glycaemic control, cardiovascular risk factors, diabetic complications, concomitant medication use and adherence to treatment recommendations were evaluated in 225 consecutive patients (45.3% women) who were comparable with respect to age, diabetes duration, and body mass index.ResultsAlthough women with T1DM had a higher total cholesterol than men, triglycerides were higher in obese men and males with HbA1c>7% than in their female counterparts. No sex differences were observed in glycaemic control and in micro- or macrovascular complications. However, the subgroup analysis showed that nephropathy was more common in obese men, hyperlipidaemic women and all hypertensive patients, whereas peripheral neuropathy was more common in hyperlipidaemic women. Retinopathy was found more frequently in women with HbA1c>7%, obese men and in both sexes with a long duration of diabetes. The multivariate analysis revealed that microvascular complications were associated with the duration of disease and BMI in both sexes and with hyperlipidaemia in males. The overall adherence to interventions according to the guidelines was higher in men than in women. This adherence was concerned particularly with co-medication in patients diagnosed with hypertension, aspirin prescription in elderly patients and the achievement of target lipid levels following the prescription of statins.ConclusionsOur data showed sex differences in lipids and overweight in patients with T1DM. Although glycaemic control and the frequency of diabetic complications were comparable between the sexes, the overall adherence to guidelines, particularly with respect to the prescription of statins and aspirin, was lower in women than in men.

The combined effect of genetic polymorphisms and clinical parameters on treatment outcome in treatment-resistant depression

For over a decade, the European Group for the Study of Resistant Depression (GSRD) has examined single nucleotide polymorphisms (SNP) and clinical parameters in regard to treatment outcome. However, an interaction based model combining these factors has not been established yet. Regarding the low effect of individual SNPs, a model investigating the interactive role of SNPs and clinical variables in treatment-resistant depression (TRD) seems auspicious. Thus 225 patients featured in previous work of the GSRD were enrolled in this investigation. According to data availability and previous positive results, 12 SNPs in HTR2A, COMT, ST8SIA2, PPP3CC and BDNF as well as 8 clinical variables featured in other GSRD studies were chosen for this investigation. Random forests algorithm were used for variable shrinkage and k-means clustering for surfacing variable characteristics determining treatment outcome. Using these machine learning and clustering algorithms, we detected a set of 3 SNPs and a clinical variable that was significantly associated with treatment response. About 62% of patients exhibiting the allelic combination of GG-GG-TT for rs6265, rs7430 and rs6313 of the BDNF, PPP3CC and HTR2A genes, respectively, and without melancholia showed a HAM-D decline under 17 compared to about 34% of the whole study sample. Our random forests prediction model for treatment outcome showed that combining clinical and genetic variables gradually increased the prediction performance recognizing correctly 25% of responders using all 4 factors. Thus, we could confirm our previous findings and furthermore show the strength of an interaction-based model combining statistical algorithms in identifying and operating treatment predictors.

Socio-demographic and clinical predictors of treatment resistant depression: A prospective European multicenter study

BACKGROUND Few studies investigated socio-demographic and clinical predictors of non response and remission in treatment resistant depression (TRD) in the case of failure of more than two adequate antidepressant (AD) trial. The primary aim of this study was to investigate socio-demographic and clinical predictors of TRD defined as the lack of response to at least three adequate AD treatments, two of which prospectively evaluated. As secondary aims, we also investigated predictors of non response and remission to: (1) at least two adequate AD treatment (one of which prospectively assessed); (2) at least one adequate and retrospectively assessed AD treatment. METHODS In the context of a European multicenter project, 407 major depressive disorder (MDD) patients who failed to respond to a previous AD treatment were recruited for a 2 stage trial, firstly receiving venlafaxine and then escitalopram. MINI, HRSD, MADRS, UKU, CGI-S and CGI-I were administered. RESULTS Ninety eight subjects (27.61%) were considered as resistant to three AD treatments. Clinical predictors were: longer duration and higher severity of the current episode (p=0.004; ES=0.24; p=0.01; RR=1.41, respectively), outpatient status (p=0.04; RR=1.58), higher suicidal risk level (p=0.02; RR=1.49), higher rate of the first/second degree psychiatric antecedents (MDD and others) (p=0.04; RR=1.31, p=0.03; RR=1.32 respectively) and side effects during treatments (p=0.002; RR=2.82). Multivariate analyses underlined the association between TRD and the severity of the current episode (p=0.04). As for secondary outcomes, predicting factors were partially overlapping. LIMITATIONS The limited sample size and specific drugs used limit present findings. CONCLUSION Subjects with a high degree of resistance to AD treatments show specific features which may guide the clinicians to the choice of more appropriate therapies at baseline.

Effects of norepinephrine transporter gene variants on NET binding in ADHD and healthy controls investigated by PET

Attention deficit hyperactivity disorder (ADHD) is a heterogeneous disorder with a strong genetic component. The norepinephrine transporter (NET) is a key target for ADHD treatment and the NET gene has been of high interest as a possible modulator of ADHD pathophysiology. Therefore, we conducted an imaging genetics study to examine possible effects of single nucleotide polymorphisms (SNPs) within the NET gene on NET nondisplaceable binding potential (BPND) in patients with ADHD and healthy controls (HCs). Twenty adult patients with ADHD and 20 HCs underwent (S,S)‐[18F]FMeNER‐D2 positron emission tomography (PET) and were genotyped on a MassARRAY MALDI‐TOF platform using the Sequenom iPLEX assay. Linear mixed models analyses revealed a genotype‐dependent difference in NET BPND between groups in the thalamus and cerebellum. In the thalamus, a functional promoter SNP (−3081 A/T) and a 5′‐untranslated region (5′UTR) SNP (−182 T/C), showed higher binding in ADHD patients compared to HCs depending on the major allele. Furthermore, we detected an effect of genotype in HCs, with major allele carriers having lower binding. In contrast, for two 3′UTR SNPs (*269 T/C, *417 A/T), ADHD subjects had lower binding in the cerebellum compared to HCs depending on the major allele. Additionally, symptoms of hyperactivity and impulsivity correlated with NET BPND in the cerebellum depending on genotype. Symptoms correlated positively with cerebellar NET BPND for the major allele, while symptoms correlated negatively to NET BPND in minor allele carriers. Our findings support the role of genetic influence of the NE system on NET binding to be pertubated in ADHD. Hum Brain Mapp 37:884–895, 2016.

Pharmacological treatment strategies in unipolar depression in European tertiary psychiatric treatment centers – A pharmacoepidemiological cross-sectional multicenter study

This multicenter, cross-sectional study with retrospective assessment of treatment response evaluated the current prescription trends and pharmacological treatment strategies applied in European university/academic psychiatric centers in unipolar depression. Altogether, 1181 adult in- and outpatients with major depressive disorder (MDD) were enrolled in 9 academic sites in 8 European countries. Socio-demographic, clinical, and medication information were retrieved and the present symptom severity was assessed by the Montgomery and Åsberg Depression Rating Scale (MADRS). The symptom improvement during the current MDD episode was covered by retrospective MADRS measurements. Beyond descriptive statistics, analyses of variance (ANOVA) and Spearman correlation analyses were accomplished to determine the influence of symptom severity and treatment response on the prescription patterns. 53.4% of all MDD patients received a selective serotonin reuptake inhibitor (SSRI) and 23.6% a serotonin-norepinephrine reuptake inhibitor (SNRI) as first-line treatment. The majority of participants (59.4%) were treated with polypharmaceutical strategies (median: 2 psychiatric compounds per patient) and for the number of individual drugs we found a significant correlation with the current MADRS total score and the MADRS total score change during the present depressive episode. Benzodiazepines (33.2% of patients), antidepressants (29.0%), antipsychotics (24.2%), and mood stabilizers (10.1%) were the most frequently prescribed adjunctive agents. There were no significant differences between the different psychopharmacological classes used as augmentors in terms of symptom severity and treatment response. In summary, this international cross-sectional study revealed the widespread use of polypharmaceutical treatment strategies in European tertiary psychiatric treatment centers for the management of MDD.

Quantification of Task-Specific Glucose Metabolism with Constant Infusion of 18F-FDG

The investigation of cerebral metabolic rate of glucose (CMRGlu) at baseline and during specific tasks previously required separate scans with the drawback of high intrasubject variability. We aimed to validate a novel approach to assessing baseline glucose metabolism and task-specific changes in a single measurement with a constant infusion of 18F-FDG. Methods: Fifteen healthy subjects underwent two PET measurements with arterial blood sampling. As a reference, baseline CMRGlu was quantified from a 60-min scan after 18F-FDG bolus application using the Patlak plot (eyes closed). For the other scan, a constant radioligand infusion was applied for 95 min, during which the subjects opened their eyes at 10–20 min and 60–70 min and tapped their right thumb to their fingers at 35–45 min and 85–95 min. The constant-infusion scan was quantified in two steps. First, the general linear model was used to fit regional time–activity curves with regressors for baseline metabolism, task-specific changes for the eyes-open and finger-tapping conditions, and movement parameters. Second, the Patlak plot was used for quantification of CMRGlu. Multiplication of the baseline regressor by β-values from the general linear model yielded regionally specific time–activity curves for baseline metabolism. Further, task-specific changes in metabolism are directly proportional to changes in the slope of the time–activity curve and hence to changes in CMRGlu. Results: Baseline CMRGlu from the constant-infusion scan matched that from the bolus application (test–retest variability, 1.1% ± 24.7%), which was not the case for a previously suggested approach (variability, −39.9% ± 25.2%, P < 0.001). Task-specific CMRGlu increased in the primary visual and motor cortices for eyes open and finger tapping, respectively (P < 0.05, familywise error–corrected), with absolute changes of up to 2.1 μmol/100 g/min and 6.3% relative to baseline. For eyes open, a decreased CMRGlu was observed in default-mode regions (P < 0.05, familywise error–corrected). CMRGlu quantified with venous blood samples (n = 6) showed excellent agreement with results obtained from arterial samples (r > 0.99). Conclusion: Baseline glucose metabolism and task-specific changes can be quantified in a single measurement with constant infusion of 18F-FDG and venous blood sampling. The high sensitivity and regional specificity of the approach offer novel possibilities for functional and multimodal brain imaging.

Altered interregional molecular associations of the serotonin transporter in attention deficit/hyperactivity disorder assessed with PET.

Altered serotonergic neurotransmission has been found to cause impulsive and aggressive behavior, as well as increased motor activity, all exemplifying key symptoms of ADHD. The main objectives of this positron emission tomography (PET) study were to investigate the serotonin transporter binding potential (SERT BPND) in patients with ADHD and to assess associations of SERT BPND between the brain regions. 25 medication‐free patients with ADHD (age ± SD; 32.39 ± 10.15; 10 females) without any psychiatric comorbidity and 25 age and sex matched healthy control subjects (33.74 ± 10.20) were measured once with PET and the highly selective and specific radioligand [11C]DASB. SERT BPND maps in nine a priori defined ROIs exhibiting high SERT binding were compared between groups by means of a linear mixed model. Finally, adopted from structural and functional connectivity analyses, we performed correlational analyses using regional SERT binding potentials to examine molecular interregional associations between all selected ROIs. We observed significant differences in the interregional correlations between the precuneus and the hippocampus in patients with ADHD compared to healthy controls, using SERT BPND of the investigated ROIs (P < 0.05; Bonferroni corrected). When correlating SERT BPND and age in the ADHD and the healthy control group, we confirmed an age‐related decline in brain SERT binding in the thalamus and insula (R2 = 0.284, R2 = 0.167, Ps < 0.05; Bonferroni corrected). The results show significantly different interregional molecular associations of the SERT expression for the precuneus with hippocampus in patients with ADHD, indicating presumably altered functional coupling. Altered interregional coupling between brain regions might be a sensitive approach to demonstrate functional and molecular alterations in psychiatric conditions. Hum Brain Mapp 38:792–802, 2017.

Subcortical gray matter changes in transgender subjects after long-term cross-sex hormone administration

Sex-steroid hormones are primarily involved in sexual differentiation and development and are thought to underlie processes related to cognition and emotion. However, divergent results have been reported concerning the effects of hormone administration on brain structure including side effects like brain atrophy and dementia. Cross-sex hormone therapy in transgender subjects offers a unique model for studying the effects of sex hormones on the living human brain. In this study, 25 Female-to-Male (FtM) and 14 Male-to-Female (MtF) subjects underwent MRI examinations at baseline and after a period of at least 4-months of continuous cross-sex hormone administration. While MtFs received estradiol and anti-androgens, FtM subjects underwent high-dose testosterone treatment. The longitudinal processing stream of the FreeSurfer software suite was used for the automated assessment and delineation of brain volumes to assess the structural changes over the treatment period of cross-sex hormone administration. Most prominent results were found for MtFs receiving estradiol and anti-androgens in the form of significant decreases in the hippocampal region. Further analysis revealed that these decreases were reflected by increases in the ventricles. Additionally, changes in progesterone levels correlated with changes in gray matter structures in MtF subjects. In line with prior studies, our results indicate hormonal influences on subcortical structures related to memory and emotional processing. Additionally, this study adds valuable knowledge that progesterone may play an important role in this process.

Pleiotropic genes in psychiatry: Calcium channels and the stress-related FKBP5 gene in antidepressant resistance

&NA; A candidate gene and a genome‐wide approach were combined to study the pharmacogenetics of antidepressant response and resistance. Investigated genes were selected on the basis of pleiotropic effect across psychiatric phenotypes in previous genome‐wide association studies and involvement in antidepressant response. Three samples with major depressive disorder (total = 671) were genotyped for 44 SNPs in 8 candidate genes (CACNA1C, CACNB2, ANK3, GRM7, TCF4, ITIH3, SYNE1, FKBP5). Phenotypes were response/remission after 4 weeks of treatment and treatment‐resistant depression (TRD). Genome‐wide data from STAR*D were used to replicate findings for response/remission (n = 1409) and TRD (n = 620). Pathways including the most promising candidate genes were investigated in STAR*D for involvement in TRD. FKBP5 polymorphisms showed replicated but nominal associations with response, remission or TRD. CACNA1C rs1006737 and rs10848635 were the only polymorphisms that survived multiple‐testing correction. In STAR*D the best pathway associated with TRD included CACNA1C (GO:0006942, permutated p = 0.15). Machine learning models showed that independent SNPs in this pathway predicted TRD with a mean sensitivity of 0.83 and specificity of 0.56 after 10‐fold cross validation repeated 100 times. FKBP5 polymorphisms appear good candidates for inclusion in antidepressant pharmacogenetic tests. Pathways including the CACNA1C gene may be involved in TRD and they may provide the base for developing multi‐marker predictors of TRD. HighlightsFKBP5 SNPs were nominally associated with antidepressant response, remission and resistance across different samples.CACNA1C rs1006737 and rs10848635 were associated with antidepressant response.Pathways including CACNA1C may be useful to develop multi‐marker predictors of antidepressant resistance.

Association of Protein Distribution and Gene Expression Revealed by PET and Post-Mortem Quantification in the Serotonergic System of the Human Brain.

Abstract Regional differences in posttranscriptional mechanisms may influence in vivo protein densities. The association of positron emission tomography (PET) imaging data from 112 healthy controls and gene expression values from the Allen Human Brain Atlas, based on post‐mortem brains, was investigated for key serotonergic proteins. PET binding values and gene expression intensities were correlated for the main inhibitory (5‐HT1A) and excitatory (5‐HT2A) serotonin receptor, the serotonin transporter (SERT) as well as monoamine oxidase‐A (MAO‐A), using Spearmans correlation coefficients (rs) in a voxel‐wise and region‐wise analysis. Correlations indicated a strong linear relationship between gene and protein expression for both the 5‐HT1A (voxel‐wise rs = 0.71; region‐wise rs = 0.93) and the 5‐HT2A receptor (rs = 0.66; 0.75), but only a weak association for MAO‐A (rs = 0.26; 0.66) and no clear correlation for SERT (rs = 0.17; 0.29). Additionally, region‐wise correlations were performed using mRNA expression from the HBT, yielding comparable results (5‐HT1Ars = 0.82; 5‐HT2Ars = 0.88; MAO‐A rs = 0.50; SERT rs = −0.01). The SERT and MAO‐A appear to be regulated in a region‐specific manner across the whole brain. In contrast, the serotonin‐1A and ‐2A receptors are presumably targeted by common posttranscriptional processes similar in all brain areas suggesting the applicability of mRNA expression as surrogate parameter for density of these proteins.