Serotonin Transporter Gene Promoter Hypomethylation as a Predictor of Antidepressant Treatment Response in Major Depression: A Replication Study.

BACKGROUND: The serotonin transporter gene (SLC6A4; 5-HTT; SERT) is considered a prime candidate in pharmacogenetic research in major depressive disorder (MDD). Besides genetic variation, recent advances have spotlighted the involvement of epigenetic mechanisms such as DNA methylation in predicting antidepressant treatment response in "pharmaco-epigenetic" approaches. In MDD, lower SLC6A4 promoter methylation has been suggested to predict impaired response to serotonergic antidepressants. The present study sought to replicate and extend this finding in a large, independent sample of MDD patients. METHODS: The sample comprised n = 236 Caucasian patients with MDD receiving antidepressant medication in a naturalistic treatment setting. Functional DNA methylation of 9 CpG sites located in the SLC6A4 promoter region was analyzed via direct sequencing of sodium bisulfite- treated DNA extracted from blood cells. Patients were assessed over the course of a 6-week in-patient treatment using the Hamilton Depression Scale (HAM-D). RESULTS: Results confirm relative SLC6A4 hypomethylation to predict impaired antidepressant response both dimensionally and categorically (HAM-D reductions < 50%) and to furthermore be indicative of nonremission (HAM-D > 7). This also held true in a homogenous subgroup of patients continuously treated with selective serotonin reuptake inhibitors or serotonin/noradrenaline reuptake inhibitors (n = 110). CONCLUSIONS: Impaired response to serotonergic antidepressants via SLC6A4 hypomethylation may be conveyed by increased gene expression and consequently decreased serotonin availability, which may counteract the effects of serotonergic antidepressants. The present results could in the future inform clinical decision-making towards a more personalized treatment of MDD.

[Pharmacotherapy of anxiety disorders-Guideline-conform treatment and new developments]. / Pharmakotherapie von Angsterkrankungen ­ leitliniengerechte Therapie und Neuentwicklungen.

Besides cognitive behavioral therapy (CBT), psychopharmacotherapy belongs to the first-line treatment approaches for anxiety disorders according to all national and international guidelines. According to studies and meta-analyses, modern antidepressants in particular have been proven to be effective. Depending on the substance, there are approvals for panic disorder, generalized anxiety disorder and social phobia. There are also approvals for other substance groups, e.g. anticonvulsants for generalized anxiety disorder. Benzodiazepines should be used with caution in view of the risk of dependency. Although effective and well-tolerated medications are available, up to 30% of patients still do not respond or do not respond adequately to treatment. Consequently, research efforts to develop new substances are important. Based on a better understanding of the complex neurobiological mechanisms underlying anxiety disorders, a large number of substances are currently undergoing clinical trials. Modulators of current and new transmitter systems, in particular the glutamatergic and the endocannabinoid systems as well as neuropeptides, are being discussed as innovative substances. Strategies are also being investigated which, in combination with psychotherapy, aim at optimizing fear extinction memory. First studies are also underway on the use of psychedelic agents in combination with psychotherapy for anxiety.

Effects of physical activity on cognitive performance: a controlled clinical study in depressive patients.

Physical activity is a common adjunctive therapy in psychiatric and psychosomatic hospitals. In the present study, we assessed the effects of an exercise program, integrated into routine inpatient treatment, on cognitive performance and subjective severity of depression in a sample of patients suffering from major depression. We randomized n = 38 patients with unipolar depression to either physical exercise (n = 18) or occupational therapy as an active control treatment (n = 20). Both treatments were delivered in group format over a period of 3-4 weeks. Data indicate that there were significant improvements of cognitive functions and depressive symptoms in both groups, with specific treatment effects in reaction time and in short-term verbal memory favoring the physical activity group. In conclusion, we found physical exercise to be a feasible, easy-to-implement add-on therapy for depressive patients with promising effects on cognitive performance. However, these results need to be replicated in larger samples with an extended follow-up.

GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder.

The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 × 10-8; rs191260602, P=3.9 × 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 × 10-4) and rs7688285 (P=7.6 × 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.

Effects of electroconvulsive therapy on amygdala function in major depression - a longitudinal functional magnetic resonance imaging study.

BACKGROUND: Electroconvulsive therapy (ECT) is one of the most effective treatments for severe depression. However, little is known regarding brain functional processes mediating ECT effects. METHOD: In a non-randomized prospective study, functional magnetic resonance imaging data during the automatic processing of subliminally presented emotional faces were obtained twice, about 6 weeks apart, in patients with major depressive disorder (MDD) before and after treatment with ECT (ECT, n = 24). Additionally, a control sample of MDD patients treated solely with pharmacotherapy (MED, n = 23) and a healthy control sample (HC, n = 22) were obtained. RESULTS: Before therapy, both patient groups equally showed elevated amygdala reactivity to sad faces compared with HC. After treatment, a decrease in amygdala activity to negative stimuli was discerned in both patient samples indicating a normalization of amygdala function, suggesting mechanisms potentially unspecific for ECT. Moreover, a decrease in amygdala activity to sad faces was associated with symptomatic improvements in the ECT sample (r spearman = -0.48, p = 0.044), and by tendency also for the MED sample (r spearman = -0.38, p = 0.098). However, we did not find any significant association between pre-treatment amygdala function to emotional stimuli and individual symptom improvement, neither for the ECT sample, nor for the MED sample. CONCLUSIONS: In sum, the present study provides first results regarding functional changes in emotion processing due to ECT treatment using a longitudinal design, thus validating and extending our knowledge gained from previous treatment studies. A limitation was that ECT patients received concurrent medication treatment.

Allelic variation in CRHR1 predisposes to panic disorder: evidence for biased fear processing.

Corticotropin-releasing hormone (CRH) is a major regulator of the hypothalamic-pituitary-adrenal axis. Binding to its receptor CRHR1 triggers the downstream release of the stress response-regulating hormone cortisol. Biochemical, behavioral and genetic studies revealed CRHR1 as a possible candidate gene for mood and anxiety disorders. Here we aimed to evaluate CRHR1 as a risk factor for panic disorder (PD). Allelic variation of CRHR1 was captured by 9 single-nucleotide polymorphisms (SNPs), which were genotyped in 531 matched case/control pairs. Four SNPs were found to be associated with PD, in at least one sub-sample. The minor allele of rs17689918 was found to significantly increase risk for PD in females after Bonferroni correction and furthermore decreased CRHR1 mRNA expression in human forebrains and amygdalae. When investigating neural correlates underlying this association in patients with PD using functional magnetic resonance imaging, risk allele carriers of rs17689918 showed aberrant differential conditioning predominantly in the bilateral prefrontal cortex and safety signal processing in the amygdalae, arguing for predominant generalization of fear and hence anxious apprehension. Additionally, the risk allele of rs17689918 led to less flight behavior during fear-provoking situations but rather increased anxious apprehension and went along with increased anxiety sensitivity. Thus reduced gene expression driven by CRHR1 risk allele leads to a phenotype characterized by fear sensitization and hence sustained fear. These results strengthen the role of CRHR1 in PD and clarify the mechanisms by which genetic variation in CRHR1 is linked to this disorder.

Is prepulse modification altered by continuous theta burst stimulation? DAT1 genotype and motor threshold interact on prepulse modification following brain stimulation.

Previous studies suggest an inhibitory top-down control of the amygdala by the prefrontal cortex (PFC). Both brain regions play a role in the modulation of prepulse modification (PPM) of the acoustic startle response by a pre-stimulus. Repetitive transcranial magnetic stimulation (rTMS) can modulate the activity of the PFC and might thus affect PPM. This study tested the effect of inhibitory rTMS on PPM accounting for a genetic variant of the dopamine transporter gene (DAT1). Healthy participants (N = 102) were stimulated with continuous theta burst stimulation (cTBS, an intense form of inhibitory rTMS) or sham treatment over the right PFC. Afterwards, during continuous presentation of a background white noise a louder noise burst was presented either alone (control startle) or preceded by a prepulse. Participants were genotyped for a DAT1 variable number tandem repeat (VNTR) polymorphism. Two succeeding sessions of cTBS over the right PFC (2 × 600 stimuli with a time lag of 15 min) attenuated averaged prepulse inhibition (PPI) in participants with a high resting motor threshold. An attenuation of PPI induced by prepulses with great distances to the pulse (480, 2000 ms) was observed following active cTBS in participants that were homozygous carriers of the 10-repeat-allele of the DAT1 genotype and had a high resting motor threshold. Our results confirm the importance of the prefrontal cortex for the modulation of PPM. The effects were observed in participants with a high resting motor threshold only, probably because they received a higher dose of cTBS. The effects in homozygous carriers of the DAT1 10-repeat allele confirm the relevance of dopamine for PPM. Conducting an exploratory study we decided against the use of a correction for multiple testing.

Differing brain structural correlates of familial and environmental risk for major depressive disorder revealed by a combined VBM/pattern recognition approach.

BACKGROUND: Neuroimaging traits of either familial or environmental risk for major depressive disorder (MDD) have been interpreted as possibly useful vulnerability markers. However, the simultaneous occurrence of familial and environmental risk might prove to be a major obstacle in the attempt of recent studies to confine the precise impact of each of these conditions on brain structure. Moreover, the exclusive use of group-level analyses does not permit prediction of individual illness risk which would be the basic requirement for the clinical application of imaging vulnerability markers. Hence, we aimed to distinguish between brain structural characteristics of familial predisposition and environmental stress by using both group- and individual-level analyses. METHOD: We investigated grey matter alterations between 20 healthy control subjects (HC) and 20 MDD patients; 16 healthy first-degree relatives of MDD patients (FH+) and 20 healthy subjects exposed to former childhood maltreatment (CM+) by using a combined VBM/pattern recognition approach. RESULTS: We found similar grey matter reductions in the insula and the orbitofrontal cortex in patients and FH+ subjects and in the hippocampus in patients and CM+ subjects. No direct overlap in grey matter alterations was found between FH+ and CM+ subjects. Pattern classification successfully detected subjects at risk for the disease even by strictly focusing on morphological traits of MDD. CONCLUSIONS: Familial and environmental risk factors for MDD are associated with differing morphometric anomalies. Pattern recognition might be a promising instrument in the search for and future application of vulnerability markers for MDD.

Multimodal imaging of a tescalcin (TESC)-regulating polymorphism (rs7294919)-specific effects on hippocampal gray matter structure.

In two large genome-wide association studies, an intergenic single-nucleotide polymorphism (SNP; rs7294919) involved in TESC gene regulation has been associated with hippocampus volume. Further characterization of neurobiological effects of the TESC gene is warranted using multimodal brain-wide structural and functional imaging. Voxel-based morphometry (VBM8) was used in two large, well-characterized samples of healthy individuals of West-European ancestry (Münster sample, N=503; SHIP-TREND, N=721) to analyze associations between rs7294919 and local gray matter volume. In subsamples, white matter fiber structure was investigated using diffusion tensor imaging (DTI) and limbic responsiveness was measured by means of functional magnetic resonance imaging (fMRI) during facial emotion processing (N=220 and N=264, respectively). Furthermore, gene x environment (G × E) interaction and gene x gene interaction with SNPs from genes previously found to be associated with hippocampal size (FKBP5, Reelin, IL-6, TNF-α, BDNF and 5-HTTLPR/rs25531) were explored. We demonstrated highly significant effects of rs7294919 on hippocampal gray matter volumes in both samples. In whole-brain analyses, no other brain areas except the hippocampal formation and adjacent temporal structures were associated with rs7294919. There were no genotype effects on DTI and fMRI results, including functional connectivity measures. No G × E interaction with childhood maltreatment was found in both samples. However, an interaction between rs7294919 and rs2299403 in the Reelin gene was found that withstood correction for multiple comparisons. We conclude that rs7294919 exerts highly robust and regionally specific effects on hippocampal gray matter structures, but not on other neuropsychiatrically relevant imaging markers. The biological interaction between TESC and RELN pointing to a neurodevelopmental origin of the observed findings warrants further mechanistic investigations.

[Pharmacotherapy of Anxiety Disorders]. / Pharmakotherapie bei Angsterkrankungen.

Anxiety disorders belong to the most frequent psychiatric disorders according to epidemiological studies and are associated with a high economic burden. Panic disorder, generalized anxiety disorder, social anxiety disorder, and specific phobia belong to the most important clinical disorders. The etiology is complex, including genetic, neurobiological as well as psychosocial factors. With regard to treatment, both psychotherapy and medication can be employed according to current treatment guidelines. With regard to psychotherapy, cognitive behavioral therapy (CBT) represents the treatment of choice. As for pharmacological treatment, in particular modern antidepressants and pregabalin are recommended. However, several recommendations have to be considered in daily clinical practice.

[Repetitive Transcranial Magnetic Stimulation (rTMS) as a Therapeutic Tool in Psychiatry - Current State of Application in Germany]. / Die repetitive transkranielle Magnetstimulation (rTMS) als therapeutische Option in der Psychiatrie ­ Stand der Anwendung in Deutschland.

The repetitive transcranial magnetic stimulation (TMS) opens new therapeutic options in neuropsychiatric disorders. The use of rTMS in depressive disorders has been most preferably investigated in clinical trials. In Germany, the application of rTMS outside of clinical trials is already increasingly common, not only for depression. Our nationwide survey in psychiatric hospitals was used to detect the current state of the application of rTMS in clinical practice, and should serve as a basis for the development of quality standards.

Driving performance and psychomotor function in depressed patients treated with agomelatine or venlafaxine.

OBJECTIVE: We conducted a randomized case-control study in depressive inpatients to assess the effects of agomelatine and venlafaxine on psychomotor functions related to driving skills and on driving performance in an on-road driving test. METHOD: 40 depressed inpatients treated with agomelatine (n = 20) or venlafaxine (n = 20) were tested before pharmacological treatment (t0), and on days 14 (t1) and 28 (t2). 20 healthy subjects were examined in the same time schedule to control for retest effects in psychomotor measures. Additionally, participants were rated in a standardized on-road driving test on day 28 by a licensed driving instructor, who was blind with respect to treatment, diagnosis and test results. RESULTS: After 4 weeks of treatment (t2) with agomelatine or venlafaxine, patients showed a significant reduction in depressive symptoms, and a distinct improvement in psychomotor functions. Controlling for retest effects in psychomotor measures, data indicate, that both patient groups significantly improved in tests measuring reactivity and stress-tolerance. Furthermore, prior discharge to outpatient treatment (day 28), 72.5% of patients were labeled abundantly fit to drive in the on-road driving test by a licensed driving instructor. However, patients did not reach the performance level of healthy controls in functional domains tested. Significant differences between treatment groups were not observed. CONCLUSION: Our results indicate that depressed inpatients treated with agomelatine or venlafaxine show a better test performance on tasks related to driving skills than do untreated depressives and could predominantly be rated as fit to drive on an actual driving test prior discharge to outpatient treatment.

[Neuropsychological treatment of cognitive deficits in substance abuse disorders, affective disorders, anxiety disorders and obsessive-compulsive disorders - current status and perspectives]. / Neuropsychologische Behandlung kognitiver Defizite bei Suchtmittel-, affektiven, Angst- und Zwangserkrankungen - Aktueller Stand und Perspektiven.

Neuropsychological treatment represents a promising therapeutic approach in the amelioration of cognitive deficits in many neuropsychiatric disorders. Cognitive impairment constitutes a core feature that often persists beyond psychopathological symptoms having a significant impact on psychosocial functioning. However, research interest and evidence of efficacy vary considerably between disease groups. Although neuropsychological treatment is frequently used in clinical practice, there are, with the exception of schizophrenia, relatively few studies on its effectiveness.

[Repetitive transcranial magnetic stimulation (rTMS) for anxiety disorders--a possible therapeutic option?]. / Repetitive transkranielle Magnetstimulation (rTMS) bei Angsterkrankungen--eine mögliche Therapieoption?

Anxiety disorders rank among the most frequent psychiatric disorders. Effective psychotherapeutic and psychopharmacological interventions exist, although a considerable number of patients does not respond to standard interventions. Repetitive transcranial magnetic stimulation (rTMS) is capable of modulating cortical activity locally and non-invasively. Therefore, rTMS is discussed as a possible alternative treatment approach in psychiatric disorders. The present paper aims to provide a systematic review of randomised controlled studies, open studies, and case reports examining the potential therapeutic effects of rTMS in anxiety disorders. Overall, these studies suggest beneficial effects of rTMS on anxiety symptoms. Nevertheless, larger randomised controlled studies are warranted to allow a more comprehensive evaluation of the therapeutic efficacy of rTMS in anxiety disorders.

Neuronal network of panic disorder: the role of the neuropeptide cholecystokinin.

Panic disorder (PD) is characterized by panic attacks, anticipatory anxiety and avoidance behavior. Its pathogenesis is complex and includes both neurobiological and psychological factors. With regard to neurobiological underpinnings, anxiety in humans seems to be mediated through a neuronal network, which involves several distinct brain regions, neuronal circuits and projections as well as neurotransmitters. A large body of evidence suggests that the neuropeptide cholecystokinin (CCK) might be an important modulator of this neuronal network. Key regions of the fear network, such as amygdala, hypothalamus, peraqueductal grey, or cortical regions seem to be connected by CCKergic pathways. CCK interacts with several anxiety-relevant neurotransmitters such as the serotonergic, GABA-ergic and noradrenergic system as well as with endocannabinoids, NPY and NPS. In humans, administration of CCK-4 reliably provokes panic attacks, which can be blocked by antipanic medication. Also, there is some support for a role of the CCK system in the genetic pathomechanism of PD with particularly strong evidence for the CCK gene itself and the CCK-2R (CCKBR) gene. Thus, it is hypothesized that genetic variants in the CCK system might contribute to the biological basis for the postulated CCK dysfunction in the fear network underlying PD. Taken together, a large body of evidence suggests a possible role for the neuropeptide CCK in PD with regard to neuroanatomical circuits, neurotransmitters and genetic factors. This review article proposes an extended hypothetical model for human PD, which integrates preclinical and clinical findings on CCK in addition to existing theories of the pathogenesis of PD.

Transcranial Direct Current Stimulation (tDCS) for major depression - Interim analysis of cloud supervised technical data from the DepressionDC trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) of prefrontal cortex regions has been reported to exert antidepressant effects, though large scale multicenter trials in major depressive disorder (MDD) supporting this notion are still lacking. Application of tDCS in multicenter settings, however, requires measurement, storage and evaluation of technical parameters of tDCS sessions not only for safety reasons but also for quality control. To address this issue, we conducted an interim analysis of supervised technical data across study centers in order to monitor technical quality of tDCS in an ongoing multicenter RCT in MDD (DepressionDC trial). METHODS: Technical data of 818 active tDCS sessions were recorded, stored in a data cloud, and analysed without violating study blinding. Impedance, voltage and current were monitored continuously with one data point recorded every second of stimulation. RESULTS: Variability of impedance was considerable (1,42 kΩ, to 8,23 kΩ), inter-individually and even more intra-individually, but did not significantly differ between the study centre in Munich and all other sites. CONCLUSION: Measurement, centralized data storage via data cloud and remote supervision of technical parameters of tDCS are feasible and proposed for future RCTs on therapeutic tDCS in multiple settings.

Therapy-refractory panic: current research areas as possible perspectives in the treatment of anxiety.

Panic disorder (PD) is characterized by recurrent panic attacks that are defined as distinct episodes of intense fear, accompanied by symptoms related to physical arousal. Because most patients interpret these symptoms as signs of serious somatic disease (e.g., a heart attack), utilization of healthcare services is high in PD sufferers. PD can become debilitating, interfering significantly with patients' lives. Fortunately, effective treatments are available, but a considerable proportion of patients do not respond sufficiently. The aim of this paper is to outline some promising research strategies aimed at improving established treatments.

Comparison of combined psycho- and pharmacotherapy with monotherapy in anxiety disorders: controversial viewpoints and clinical perspectives.

Anxiety disorders are among the most frequent psychiatric disorders. Experimental evidence supports both psychotherapy as well as pharmacotherapy as effective treatments. There is, however, a controversy concerning the efficacy of a combination of both approaches. While some studies suggest that combined treatment enhances efficacy, others report conflicting results. This article traces the positions in this debate. We present the results from two recent meta-analyses and discuss implications for clinical practice and further research. We suggest that a research strategy that strives to establish differential indications based on patient characteristics should be preferred over attempts to reach a global judgement of the question, which appears too simplistic given the complexity of the issue.

Effects of experimentally induced panic attacks on neuroimmunological markers.

Since little is known concerning regulation of immunological parameters in rapid changing psychiatric states like panic attacks, we measured cytokines at different time points in healthy subjects, which underwent experimental panic induction using the CCK-4 paradigm. Apart from a challenge related IL-6 increase, we could not observe any changes of neuroimmunological markers in relation to acute anxiety with regard to time and group. Herein we conducted for the first time a new approach to immunological research in panic disorder, suggesting immune changes are more related to long term disease stress.