Christian Scharinger

Imaging genetics of mood disorders.

Mood disorders are highly heritable and have been linked to brain regions of emotion processing. Over the past few years, an enormous amount of imaging genetics studies has demonstrated the impact of risk genes on brain regions and systems of emotion processing in vivo in healthy subjects as well as in mood disorder patients. While sufficient evidence already exists for several monaminergic genes as well as for a few non-monoaminergic genes, such as brain-derived neurotrophic factor (BDNF) in healthy subjects, many others only have been investigated in single studies so far. Apart from these studies, the present review also covers imaging genetics studies applying more complex genetic disease models of mood disorders, such as epistasis and gene-environment interactions, and their impact on brain systems of emotion processing. This review attempts to provide a comprehensive overview of the rapidly growing field of imaging genetics studies in mood disorder research.

Additive Gene–Environment Effects on Hippocampal Structure in Healthy Humans

Hippocampal volume loss has been related to chronic stress as well as genetic factors. Although genetic and environmental variables affecting hippocampal volume have extensively been studied and related to mental illness, limited evidence is available with respect to G × E interactions on hippocampal volume. The present MRI study investigated interaction effects on hippocampal volume between three well-studied functional genetic variants (COMT Val158Met, BDNF Val66Met, 5-HTTLPR) associated with hippocampal volume and a measure of environmental adversity (life events questionnaire) in a large sample of healthy humans (n = 153). All three variants showed significant interactions with environmental adversity with respect to hippocampal volume. Observed effects were additive by nature and driven by both recent as well as early life events. A consecutive analysis of hippocampal subfields revealed a spatially distinct profile for each genetic variant suggesting a specific role of 5-HTTLPR for the subiculum, BDNF Val66Met for CA4/dentate gyrus, and COMT Val158Met for CA2/3 volume changes. The present study underscores the importance of G × E interactions as determinants of hippocampal volume, which is crucial for the neurobiological understanding of stress-related conditions, such as mood disorders or post-traumatic stress disorder (PTSD).

The genetic blueprint of major depressive disorder: contributions of imaging genetics studies.

Abstract Objectives. To review neuroimaging intermediate phenotypes of MDD and their relation to genetic risk variants. Methods. A systematic literature search of peer-reviewed English language articels using PubMed (www.pubmed.org) was performed. Results. Comprehensive evidence on the influence of serotonergic genes (SLC6A4, HTR1A, MAOA, TPH2) and BDNF on the following neural intermediate phenotypes is displayed: amygdala reactivity, coupling of amygdala-anterior cingulate cortex (ACC) activity, ACC volume, hippocampal volume and serotonin receptor 1A (5-HT1A) binding potential (BP). Conclusions. Intermediate phenotypes may bridge the gap between genotype and phenotype by reducing the impreciseness of psychiatric phenotypes and yield more insights into the underlying biology.

Reduced default mode network suppression during a working memory task in remitted major depression

Insufficient default mode network (DMN) suppression was linked to increased rumination in symptomatic Major Depressive Disorder (MDD). Since rumination is known to predict relapse and a more severe course of MDD, we hypothesized that similar DMN alterations might also exist during full remission of MDD (rMDD), a condition known to be associated with increased relapse rates specifically in patients with adolescent onset. Within a cross-sectional functional magnetic resonance imaging study activation and functional connectivity (FC) were investigated in 120 adults comprising 78 drug-free rMDD patients with adolescent- (n = 42) and adult-onset (n = 36) as well as 42 healthy controls (HC), while performing the n-back task. Compared to HC, rMDD patients showed diminished DMN deactivation with strongest differences in the anterior-medial prefrontal cortex (amPFC), which was further linked to increased rumination response style. On a brain systems level, rMDD patients showed an increased FC between the amPFC and the dorsolateral prefrontal cortex, which constitutes a key region of the antagonistic working-memory network. Both whole-brain analyses revealed significant differences between adolescent-onset rMDD patients and HC, while adult-onset rMDD patients showed no significant effects. Results of this study demonstrate that reduced DMN suppression exists even after full recovery of depressive symptoms, which appears to be specifically pronounced in adolescent-onset MDD patients. Our results encourage the investigation of DMN suppression as a putative predictor of relapse in clinical trials, which might eventually lead to important implications for antidepressant maintenance treatment.

Platelet Serotonin Transporter Function Predicts Default-Mode Network Activity

Background The serotonin transporter (5-HTT) is abundantly expressed in humans by the serotonin transporter gene SLC6A4 and removes serotonin (5-HT) from extracellular space. A blood-brain relationship between platelet and synaptosomal 5-HT reuptake has been suggested, but it is unknown today, if platelet 5-HT uptake can predict neural activation of human brain networks that are known to be under serotonergic influence. Methods A functional magnetic resonance study was performed in 48 healthy subjects and maximal 5-HT uptake velocity (Vmax) was assessed in blood platelets. We used a mixed-effects multilevel analysis technique (MEMA) to test for linear relationships between whole-brain, blood-oxygen-level dependent (BOLD) activity and platelet Vmax. Results The present study demonstrates that increases in platelet Vmax significantly predict default-mode network (DMN) suppression in healthy subjects independent of genetic variation within SLC6A4. Furthermore, functional connectivity analyses indicate that platelet Vmax is related to global DMN activation and not intrinsic DMN connectivity. Conclusion This study provides evidence that platelet Vmax predicts global DMN activation changes in healthy subjects. Given previous reports on platelet-synaptosomal Vmax coupling, results further suggest an important role of neuronal 5-HT reuptake in DMN regulation.

Imaging genetics: implications for research on variable antidepressant drug response

Genetic variation of SLC6A4, HTR1A, MAOA, COMT and BDNF has been associated with depression, variable antidepressant drug responses as well as impacts on brain regions of emotion processing that are modulated by antidepressants. Pharmacogenetic studies are using psychometric outcome measures of drug response and are hampered by small effect sizes that might be overcome by the use of intermediate endophenotypes of drug response, which are suggested by imaging studies. Such an approach will not only tighten the relationship between genes and drug response, but also yield new insights into the neurobiology of depression and individual drug responses. This article provides a comprehensive overview of pharmacogenetic, imaging genetics and drug response studies, utilizing imaging techniques within the context of antidepressive drug therapy.

A multivariate approach linking reported side effects of clinical antidepressant and antipsychotic trials to in vitro binding affinities

The vast majority of approved antidepressants and antipsychotics exhibit a complex pharmacology. The mechanistic understanding of how these psychotropic medications are related to adverse drug reactions (ADRs) is crucial for the development of novel drug candidates and patient adherence. This study aims to associate in vitro assessed binding affinity profiles (39 compounds, 24 molecular drug targets) and ADRs (n=22) reported in clinical trials of antidepressants and antipsychotics (n>59.000 patients) by the use of robust multivariate statistics. Orthogonal projection to latent structures (O-PLS) regression models with reasonable predictability were found for several frequent ADRs such as nausea, diarrhea, hypotension, dizziness, headache, insomnia, sedation, sleepiness, increased sweating, and weight gain. Results of the present study support many well-known pharmacological principles such as the association of hypotension and dizziness with α1-receptor or sedation with H1-receptor antagonism. Moreover, the analyses revealed novel or hardly investigated mechanisms for common ADRs including the potential involvement of 5-HT6-antagonism in weight gain, muscarinic receptor antagonism in dizziness, or 5-HT7-antagonism in sedation. To summarize, the presented study underlines the feasibility and value of a multivariate data mining approach in psychopharmacological development of antidepressants and antipsychotics.

P02-352 - Remitted major depression is related to increased functional coupling between ventral striatum and cortical regions in resting state fMRI

Introduction Dysfunction in the basal ganglia has been related to impaired reward processing and anhedonia, a core symptom of Major Depressive Disorder (MDD). In particular, the ventral striatum including the nucleus accumbens is increasingly implicated in the pathophysiology of MDD, but evidence for a specific role during episodes of full remission is lacking so far. Objectives To investigate functional connectivity patterns of resting-state activity in patients in the remitted phase of MDD (rMDD). Aims To determine whether rMDD is related to disruptions of functional coupling between the ventral striatum and cortical regions. Methods Forty-three remitted depressed patients and thirty-five healthy controls were recruited at Medical University of Vienna, Vienna, Austria, and performed a six minute resting-state fMRI scan. Seed time series were extracted from the preprocessed data using individual masks for ventral striatum and correlated with all nodes in a surface based analysis using FreeSurfer, AFNI and SUMA. The resulting correlation coefficients were then Fishertransformed, group results were determined by comparing group mean smoothed z-scores with a two-sample ttest. Results Increased resting-state functional connectivity was revealed between ventral striatum (seed region) and anterior cingulate cortex as well as orbitofrontal cortex in the rMDD group compared to healthy controls. Conclusions Our preliminary data is in accordance with the idea that increased functional coupling between the ventral striatum and two major emotion processing regions, the anterior cingulate cortex and the orbitofrontal cortex, may represent a neural mechanism contributing to the maintenance of full remission of MDD.

Brain-derived neurotrophic factor: a peripheral biomarker for major depressive disorder and antidepressant efficacy?

Despite a plethora of studies that have linked major depressive disorder (MDD) to neuro biological alterations, its diagnosis is still exclusively based on clinical information as well as psychopathological symptoms. The currently lacking pathophysiology of MDD is at least partly originating from misconceptualized diagnostic criteria comprising a highly heterogeneous behavioral syndrome, and it is unlikely that todays operationalization of MDD is sufficiently sensitive to aggregate underlying neurobiological pathologies in a meaningful way. However, the moderate effi cacy of antidepressant drugs suggests that common biological pathways probably exist to some degree for the current biology-free diagnosis of MDD. Therefore, it appears plausible that biological markers (biomarkers) might be discovered that are related to diagnosis, treatment response or clinical course of MDD.

P02-38 - Biological alterations during remission of major depressive disorder

Introduction The natural course of Major Depressive Disorder (MDD) encompasses the occurrence of alternating intervals of major depressive episodes and remission. While several abnormalities in neural circuits related to acute MDD have been identified, the neural mechanisms underlying stable remission remain obscure. Objectives Acute MDD is characterized by increased amygdala and subgenual anterior cingulate cortex (sACC) activation and decreased connectivity between the amygdala and the sACC. Consequently, we expect those regions to be affected during remission. Aims To determine whether active counter-regulatory mechanisms are implicated in the maintenance of full remission once antidepressant treatment has been discontinued. Methods Functional and structural magnetic resonance imaging was used to measure brain activation and volume of the amygdala and the sACC. Images were obtained from 38 healthy subjects without any psychiatric life-time diagnosis and 38 gender-matched drug-free remitted MDD patients. Furthermore, correlation analyses were performed with clinical variables. Results Patients with rMDD exhibited lower activation in the amygdala and the sACC and increased functional coupling between the amygdala and sACC compared to controls. This connectivity was particularly pronounced in patients characterized by a long cumulated time of depressive episodes. Similarly, structural connectivity results showed increased association between the amygdala and sACC volume in rMDD patients compared to controls. Conclusions Remitted MDD is related to neural alterations within a neural circuit encompassing the amygdala and the sACC compared to controls. These findings suggest active counter-regulatory mechanisms likely contributing to the maintenance of remission once treatment has been discontinued.