Blood-based biomarkers predicting response to antidepressants.

Major depressive disorder is a common, serious and in some cases, life-threatening condition and affects approximately 350 million people globally. Although there is effective treatment available for it, more than 50% of the patients fail to respond to the first antidepressant they receive. The selection of a distinct treatment is still exclusively based on clinical judgment without incorporating lab-derived objective measures. However, there is growing evidence of biomarkers that it helps to improve diagnostic processes and treatment algorithms. Here genetic markers and blood-based biomarkers of the monoamine pathways, inflammatory pathways and the hypothalamic-pituitary-adrenal (HPA) axis are reviewed. Promising findings arise from studies investigating inflammatory pathways and immune markers that may identify patients suitable for anti-inflammatory based treatment regimes. Next, an early normalization of a disturbed HPA axis or depleted neurotrophic factors may predict stable treatment response. Genetic markers within the serotonergic system may identify patients who are vulnerable because of stressful life events, but evidence for guiding treatment regimes still is inconsistent. Therefore, there is still a great need for studies investigating and validating biomarkers for the prediction of treatment response to facilitate the treatment selection and shorten the time to remission and thus provide personalized medicine in psychiatry.

Plasticity of Functional MAOA Gene Methylation in Acrophobia.

Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction.

Childhood trauma dependent anxious depression sensitizes HPA axis function.

Anxious depression is a common subtype of major depressive disorder (MDD) and is associated with greater severity and poorer outcome. Alterations of the hypothalamic-pituitary-adrenal (HPA) axis, especially of the glucocorticoid receptor (GR) function, are often observed in MDD, but evidence lacks for anxious depression. Childhood adversity is known to influence both the HPA axis and risk of MDD. Therefore, we investigated GR-function in anxious depression dependent on childhood adversity. We enrolled 144 depressed in-patients (49.3% females). Anxious depression was defined using the Hamilton Depression Rating Scale (HAM-D) anxiety/somatization factor score ≥7. Blood draws were performed at 6 pm before and 3 h after 1.5 mg dexamethasone ingestion for measurement of cortisol, ACTH and blood count to assess GR-function and the immune system. In a subgroup of n = 60 FKBP5 mRNA controlled for FKBP5 genotype was measured before and after dexamethasone. Childhood adversity was evaluated using the Childhood Trauma Questionnaire (CTQ). We identified 78 patients (54.2%) with anxious depression who showed a greater severity and worse outcome. These patients were more often exposed to sexual abuse (30% vs. 16%/p = 0.04) and emotional neglect (76% vs. 58%/p = 0.02) than patients with non-anxious depression. Anxious depressed patients showed an enhanced GR-induced FKBP5 mRNA expression (F = 5.128; p = 0.03) and reduced cortisol levels, partly dependent on sexual abuse (F = 7.730; p = 0.006). Additionally, the GR-induced leukocyte response was enhanced in patients with sexual abuse (F = 7.176; p = 0.008). Anxious depression in dependence of childhood trauma is associated with heightened sensitivity of the HPA axis and the immune system which should be considered for treatment algorithms and targets.

Medial prefrontal cortex stimulation accelerates therapy response of exposure therapy in acrophobia.

BACKGROUND: Animal as well as human research indicated that the ventral medial prefrontal cortex (vmPFC) is highly relevant for fear extinction learning. Recently, we showed that targeting the vmPFC with high-frequency repetitive transcranial magnetic stimulation (rTMS) in a placebo-controlled study with 45 healthy controls induced higher prefrontal activity during extinction of conditioned stimuli (CS+) in the active compared to the sham stimulated group and better extinction learning as indicated by ratings, fear potentiated startles and skin conductance responses. OBJECTIVE: In this study, we aimed to proof our concept of accelerating extinction learning using rTMS of the mPFC in a group of anxiety disorder patients. METHODS: To specifically evaluate the impact of rTMS on exposure-based therapy, we applied a sham-controlled protocol over the vmPFC (FPz) succeeded by a virtual reality exposure therapy (VRET) in n = 20 participants with acrophobia and n = 19 controls. RESULTS: We found a significantly higher reduction in active compared to sham stimulated group for anxiety (t[37] = 2.33, p < 0.05) as well as avoidance ratings t[37] = 2.34, p < 0.05) from pre to post therapy. CONCLUSION: This study provides first clinical evidence that high-frequency rTMS over the vmPFC improves exposure therapy response of acrophobia symptoms.

Management of Budd-Chiari syndrome.

Thrombotic occlusion of the hepatic veins leads to liver dysfunction and liver failure requiring liver transplantation in advanced cases. The cause for the occlusion of the hepatic veins is not completely understood. However, several underlying conditions such as polycytemia, factor V Leiden mutation, and protein C and S deficiency are found in these patients. We here report our single-center experience with 18 consecutive patients with Budd-Chiari Syndrome (BCS) who were treated at our institution between August 1992 and June 2003. Twelve patients underwent liver transplantation, three patients received stents into the hepatic veins or vena cava, another patient was treated with TIPSS (transjugular intrahepatic postosystemic stent shunt), and one patient underwent surgical mesocaval shunting. Three patients, among those the patient with TIPSS, were put on anticoagulant therapy and are scheduled for liver transplantation. We outline the indication for an approach tailored to the stage of the disease and the adaption of the procedures with the deterioration of clinical conditions. Surgical aspects and postoperative management with a focus on liver transplantation are outlined. We conclude from our observations that the management of BCS requires an approach that exhausts conservative approaches until clinical conditions deteriorate with respect to portal hypertension or liver function. Conservative management, i.e., interventional and supportive medical therapy, has been used up to 8 years in our series, until the time for liver transplantation is reached. Liver transplantation for BCS had more complications than transplantation for other liver diseases in our series. Therefore, we propose to keep liver function stable using interventional techniques to maintain venous outflow. If venous outflow cannot be interventionally restored and liver function deteriorates or cirrhosis develops during this time course, liver transplantation is the therapy of choice.