The "missing heritability"-Problem in psychiatry: Is the interaction of genetics, epigenetics and transposable elements a potential solution?

Psychiatric disorders exhibit an enormous burden on the health care systems worldwide accounting for around one-third of years lost due to disability among adults. Their etiology is largely unknown and diagnostic classification is based on symptomatology and course of illness and not on objective biomarkers. Most psychiatric disorders are moderately to highly heritable.

Enhanced adenosine A receptor and Homer1a expression in hippocampus modulates the resilience to stress-induced depression-like behavior.

Resilience to stress is critical for the development of depression. Enhanced adenosine A receptor (AR) signaling mediates the antidepressant effects of acute sleep deprivation (SD). However, chronic SD causes long-lasting upregulation of brain AR and increases the risk of depression.

Enhanced mGlu5 Signaling in Excitatory Neurons Promotes Rapid Antidepressant Effects via AMPA Receptor Activation.

Conventional antidepressants have limited efficacy and many side effects, highlighting the need for fast-acting and specific medications. Induction of the synaptic protein Homer1a mediates the effects of different antidepressant treatments, including the rapid action of ketamine and sleep deprivation (SD). We show here that mimicking Homer1a upregulation via intravenous injection of cell-membrane-permeable TAT-Homer1a elicits rapid antidepressant effects in various tests.

The role of adenosine receptors in mood and anxiety disorders.

Adenosine receptor subtypes, first described 40 years ago, are known to regulate diverse biological functions and have a role in various conditions, such as cerebral and cardiac ischemia, immune and inflammatory disorders and cancer. In the brain, they limit potentially dangerous over excitation, but also regulate mechanisms essential in sleep and psychiatric disorders. In this review, we discuss the role of adenosine receptors in mood and anxiety disorders.

Recent insights into antidepressant therapy: Distinct pathways and potential common mechanisms in the treatment of depressive syndromes.

There is an urgent, unmet clinical need for faster and more efficient antidepressant drugs with higher response rates. In animal models of depression it was shown in the last few years that inhibition of three signaling molecules (BDNF, p11 and Homer1a) prevents efficacy of antidepressant therapy. These data not only show the crucial role of these factors for the treatment of depression, but may also point towards a better understanding of the molecular changes responsible for successful antidepressant therapy.

Alterations in Cerebrospinal Fluid in Patients with Bipolar Syndromes.

Bipolar disorder (BD) is a severe and lifelong condition. Primary endogenic polygenetic forms are common. Secondary organic forms have received increasing interest recently due to the detection of immunological encephalopathies that mimic various psychiatric syndromes, including BD.

Randomized controlled study of early medication change for non-improvers to antidepressant therapy in major depression--The EMC trial.

Patients with Major Depressive Disorder (MDD) and no improvement after two weeks of antidepressant pharmacotherapy have a high risk of treatment failure. The aim of the study was to determine whether an early medication change (EMC) strategy is superior to a guideline-based treatment in MDD patients without improvement after two weeks of antidepressant pharmacotherapy. Eight-hundred-and-eighty-nine patients with MDD were enrolled, 879 patients received the SSRI escitalopram.

Synaptic plasticity model of therapeutic sleep deprivation in major depression.

Therapeutic sleep deprivation (SD) is a rapid acting treatment for major depressive disorder (MDD). Within hours, SD leads to a dramatic decrease in depressive symptoms in 50-60% of patients with MDD. Scientifically, therapeutic SD presents a unique paradigm to study the neurobiology of MDD.

Signaling pathways regulating Homer1a expression: implications for antidepressant therapy.

Homer1a is upregulated by several different antidepressant measures, including non-pharmacological treatments, like sleep deprivation (SD) and electroconvulsive therapy (ECT) and antidepressant drugs, such as imipramine, fluoxetine and ketamine. Homer1a induction might thus be a crucial joint mechanism for antidepressant therapy in general. However, the upstream signaling pathways that regulate or induce Homer1a expression are still not well understood.

Mechanism of microglia neuroprotection: Involvement of P2X7, TNFα, and valproic acid.

Recently, we have demonstrated that ramified microglia are neuroprotective in N-methyl-D-aspartate (NMDA)-induced excitotoxicity in organotypic hippocampal slice cultures (OHSCs). The present study aimed to elucidate the underlying neuron-glia communication mechanism. It is shown here that pretreatment of OHSC with high concentrations of adenosine 5'-triphosphate (ATP) reduced NMDA-induced neuronal death only in presence of microglia.

Adenosine Receptors Differentially Regulate the Expression of Regulators of G-Protein Signalling (RGS) 2, 3 and 4 in Astrocyte-Like Cells.

The "regulators of g-protein signalling" (RGS) comprise a large family of proteins that limit by virtue of their GTPase accelerating protein domain the signal transduction of G-protein coupled receptors. RGS proteins have been implicated in various neuropsychiatric diseases such as schizophrenia, drug abuse, depression and anxiety and aggressive behaviour. Since conditions associated with a large increase of adenosine in the brain such as seizures or ischemia were reported to modify the expression of some RGS proteins we hypothesized that adenosine might regulate RGS expression in neural cells.

P2X7-dependent, but differentially regulated release of IL-6, CCL2, and TNF-α in cultured mouse microglia.

ATP is an important regulator of microglia and its effects on microglial cytokine release are currently discussed as important contributors in a variety of brain diseases. We here analyzed the effects of ATP on the production of six inflammatory mediators (IL-6, IL-10, CCL2, IFN-γ, TNF-α, and IL-12p70) in cultured mouse primary microglia. Stimulation of P2X7 receptor by ATP (1 mM) or BzATP (500 µM) evoked the mRNA expression and release of proinflammatory cytokines IL-6, TNF-α, and the chemokine CCL2 in WT cells but not in P2X7(-/-) cells.

Genetically controlled upregulation of adenosine A(1) receptor expression enhances the survival of primary cortical neurons.

Adenosine has a key endogenous neuroprotective role in the brain, predominantly mediated by the adenosine A(1) receptor (A(1)R). This has been mainly explored using pharmacological tools and/or receptor knockout mice strains. It has long been suggested that the neuroprotective effects of A(1)R are increased following receptor upregulation, thus attenuating neuronal damage in pathological conditions.

Long-term effect of combined interpersonal psychotherapy and pharmacotherapy in a randomized trial of depressed patients.

Objective: Evaluation of the long-term benefits of combined pharmacological and psychotherapeutic depression treatment and the differential impact of early childhood trauma.

Method: A randomized trial was conducted in 124 in-patients with a diagnosis of major depressive disorder comparing 5 weeks of interpersonal psychotherapy plus pharmacotherapy (IPT) with medication plus clinical management (CM). The study included a prospective, naturalistic follow-up 3, 12 and 75 months after in-patient treatment.

The Hypomania Checklist-32 and the Mood Disorder Questionnaire as screening tools--going beyond samples of purely mood-disordered patients.

Background: Bipolar disorders are often not recognized. Several screening tools have been developed, e.g.

Rationale and design of the randomised clinical trial comparing early medication change (EMC) strategy with treatment as usual (TAU) in patients with major depressive disorder--the EMC trial.

Background: In major depressive disorder (MDD), the traditional belief of a delayed onset of antidepressants' effects has lead to the concept of current guidelines that treatment durations should be between 3-8 weeks before medication change in case of insufficient outcome. Post hoc analyses of clinical trials, however, have shown that improvement usually occurs within the first 10-14 days of treatment and that such early improvement (Hamilton Depression Rating Scale [HAMD] decrease >or=20%) has a substantial predictive value for final treatment outcome. Even more important, non-improvement (HAMD decrease <20%) after 14 days of treatment was found to be highly predictive for a poor final treatment outcome.

Time course of response to antidepressants: predictive value of early improvement and effect of additional psychotherapy.

Background: The full response to antidepressant pharmacotherapy is evident only after several weeks, but considerable improvements may already be visible within the first two weeks. Little is known about the potential influence of additional psychotherapy on the speed of response to antidepressant treatment. We have analysed in more severely depressed inpatients treated with antidepressants i) the predictive value of early improvement for later response and ii) the impact of additional psychotherapy on the time course of response.

Local stimulation of the adenosine A2B receptors induces an increased release of IL-6 in mouse striatum: an in vivo microdialysis study.

Both adenosine and interleukin-6 (IL-6) have been implicated in the pathophysiology of, e.g., epileptic seizures, traumatic brain injury, and affective disorders.

Efficacy of Interpersonal Psychotherapy plus pharmacotherapy in chronically depressed inpatients.

Background: Clinical guidelines recommend the combination of pharmaco- and psychotherapy for the treatment of chronic depression, although there are only a few studies supporting an additive effect of psychotherapy.

Methods: Forty-five inpatients with a chronic Major Depressive Disorder were randomized to 5 weeks of either Interpersonal Psychotherapy (IPT) modified for an inpatient setting (15 individual and 8 group sessions) plus pharmacotherapy or to medication plus Clinical Management (CM). The 17-item Hamilton Rating Scale for Depression was the primary outcome measure.

An intensive treatment program of interpersonal psychotherapy plus pharmacotherapy for depressed inpatients: acute and long-term results.

Objective: The purpose of this article was to determine the relative efficacy of a psychotherapy program when combined with pharmacotherapy versus medication and clinical management in more severely depressed patients.

Method: A randomized controlled trial was conducted in 124 hospitalized patients with DSM-IV major depressive disorder that compared 5 weeks of interpersonal psychotherapy modified for depressed inpatients (15 individual and eight group sessions) plus pharmacotherapy with a regimen that involved medication plus intensive clinical management. The study included a prospective, naturalistic follow-up 3 and 12 months after acute treatment in 97 of 105 treatment completers.

Stress, personality and depressive symptoms in a 6.5 year follow-up of subjects at familial risk for affective disorders and controls.

Background: The aim of the study was to identify risk factors in subjects at risk for depressive disorders and controls.

Methods: In a 6.5 year follow-up study we examined the effects of personality (neuroticism, frustration intolerance, rigidity, melancholic type), adverse life events and chronic difficulties on depressive symptoms in 89 high-risk subjects (HRS, siblings and children of patients suffering from an affective disorder), without any mental illness at wave 1 (T1), and 49 controls without any personal and family history of psychiatric disorder at T1.

Sodium-myo-inositol co-transporter (SMIT-1) mRNA is increased in neutrophils of patients with bipolar 1 disorder and down-regulated under treatment with mood stabilizers.

Recent in-vitro data indicate that depletion of neural cells of myo-inositol by virtue of down-regulation of the high-affinity sodium-myo-inositol co-transporter (SMIT) may be a common mechanism of action of the mood stabilizers lithium, valproate and carbamazepine. The authors sought to investigate whether or not down-regulation of SMIT also occurs in vivo in bipolar patients. Expression of SMIT mRNA was measured in neutrophils of bipolar patients either unmedicated or treated with lithium salts or valproate and in neutrophils of unmedicated, matched healthy controls using quantitative real-time PCR.