Role of Brain Imaging in Drug Development for Psychiatry.

Background: Over the last decades, many brain imaging studies have contributed to new insights in the pathogenesis of psychiatric disease. However, in spite of these developments, progress in the development of novel therapeutic drugs for prevalent psychiatric health conditions has been limited.

Objective: In this review, we discuss translational, diagnostic and methodological issues that have hampered drug development in CNS disorders with a particular focus on psychiatry.

Major depressive disorder is associated with changes in a cluster of serum and urine biomarkers.

Major Depressive Disorder (MDD) is a heterogeneous disorder with a considerable symptomatic overlap with other psychiatric and somatic disorders. This study aims at providing evidence for association of a set of serum and urine biomarkers with MDD. We analyzed urine and serum samples of 40 MDD patients and 47 age- and sex-matched controls using 40 potential MDD biomarkers (21 serum biomarkers and 19 urine biomarkers).

The Psychobiology of Authentic and Simulated Dissociative Personality States: The Full Monty.

The etiology of dissociative identity disorder (DID) remains a topic of debate. Proponents of the fantasy model and the trauma model of DID have both called for more empirical research. To this end, the current study presents new and extended data analyses of a previously published H2O positron emission tomography imaging study.

Efficacy and safety of pregabalin in generalised anxiety disorder: A critical review of the literature.

The aim of this review is to summarise the literature on the efficacy and safety of pregabalin for the treatment of generalised anxiety disorder (GAD). Of 241 literature citations, 13 clinical trials were identified that were specifically designed to evaluate the efficacy and safety of pregabalin in GAD, including 11 randomised double-blind trials and two open-label studies. Pregabalin efficacy has been consistently demonstrated across the licensed dose range of 150-600 mg/day.

Serotonin-2C antagonism augments the effect of citalopram on serotonin and dopamine levels in the ventral tegmental area and nucleus accumbens.

Many patients with major depression do not respond to selective serotonin reuptake inhibitors (SSRIs). Lack of response could be due to inhibition of dopamine (DA) release by serotonin (5-HT) through 5-HT2C receptors. Combining an SSRI with a 5-HT2C antagonist may result in improved efficacy by causing simultaneous increases of 5-HT and DA.

Opposite brain emotion-regulation patterns in identity states of dissociative identity disorder: a PET study and neurobiological model.

Imaging studies in posttraumatic stress disorder (PTSD) have shown differing neural network patterns between hypo-aroused/dissociative and hyper-aroused subtypes. Since dissociative identity disorder (DID) involves different emotional states, this study tests whether DID fits aspects of the differing brain-activation patterns in PTSD. While brain activation was monitored using positron emission tomography, DID individuals (n=11) and matched DID-simulating healthy controls (n=16) underwent an autobiographic script-driven imagery paradigm in a hypo-aroused and a hyper-aroused identity state.

Acute social defeat does not alter cerebral 5-HT2A receptor binding in male Wistar rats.

It has been hypothesized that effects of uncontrollable stress on serotonin receptor expression contribute to the etiology of stress-related disorders like depression. While the serotonin-2A receptors (5-HT2A R) are thought to be important in this context, only few studies examined effects of stress on this receptor subtype. In this study, we therefore assessed acute and long-term changes in 5HT2A R binding after social defeat stress in rats.

Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology.

This revision of the 2005 British Association for Psychopharmacology guidelines for the evidence-based pharmacological treatment of anxiety disorders provides an update on key steps in diagnosis and clinical management, including recognition, acute treatment, longer-term treatment, combination treatment, and further approaches for patients who have not responded to first-line interventions. A consensus meeting involving international experts in anxiety disorders reviewed the main subject areas and considered the strength of supporting evidence and its clinical implications. The guidelines are based on available evidence, were constructed after extensive feedback from participants, and are presented as recommendations to aid clinical decision-making in primary, secondary and tertiary medical care.

Analysis of cognition, motor performance and anxiety in young and aged tumor necrosis factor alpha receptor 1 and 2 deficient mice.

TNF-α plays important functional roles in the central nervous system during normal physiological circumstances via intricate signaling mechanisms between its receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Although the roles of TNFR1 and TNFR2 in the diseased brain have received considerable attention, their functions on behavior and cognition in a non-inflammatory physiological aged environment are still unknown. In the present study we investigated the functional roles of TNFR1 and TNFR2 in learning and memory, motor performance and anxiety-like behavior via several behavioral and cognitive assessments in young and aged mice, deficient of either TNFR1 or TNFR2.

Chronic stress-induced changes in the rat brain: role of sex differences and effects of long-term tianeptine treatment.

Growing evidence suggests neuroplasticity changes are pivotal in both the occurrence and treatment of affective disorders. Abnormal expression and/or phosphorylation of numerous plasticity-related proteins have been observed in depression, while prolonged antidepressant treatment has been associated with the attenuation of stress-mediated effects on dendritic remodeling and adult hippocampal neurogenesis in experimental animals. This study explores the neurobiological adaptations induced by chronic stress and/or long-term tianeptine treatment.

Reduced spontaneous but relatively normal deliberate vicarious representations in psychopathy.

Psychopathy is a personality disorder associated with a profound lack of empathy. Neuroscientists have associated empathy and its interindividual variation with how strongly participants activate brain regions involved in their own actions, emotions and sensations while viewing those of others. Here we compared brain activity of 18 psychopathic offenders with 26 control subjects while viewing video clips of emotional hand interactions and while experiencing similar interactions.

Rate of improvement during and across three treatments for panic disorder with or without agoraphobia: cognitive behavioral therapy, selective serotonin reuptake inhibitor or both combined.

Background: Existing literature on panic disorder (PD) yields no data regarding the differential rates of improvement during Cognitive Behavioral Therapy (CBT), Selective Serotonin Reuptake Inhibitor (SSRI) or both combined (CBT+SSRI).

Method: Patients were randomized to CBT, SSRI or CBT+SSRI which each lasted one year including three months of medication taper. Participating patients kept record of the frequency of panic attacks throughout the full year of treatment.

Analysis of 5-HT(2A) receptor binding with [(11)C]MDL 100907 in rats: optimization of kinetic modeling.

Purpose: Preclinical positron emission tomography studies are important to follow disease progression and develop new pharmacological agents. We investigated whether kinetic modeling of 5-HT2A tracer [(11)C]MDL 100907 is possible in rats.

Procedures And Results: Kinetic modeling with either metabolite-corrected plasma curve or with the cerebellum as a reference tissue resulted in a good correlation of nondisplaceable binding potential (BPND) calculated from a two-tissue compartment model (2TCM) or different reference tissue models.

Antiaggressive activity of central oxytocin in male rats.

Rationale: A substantial body of research suggests that the neuropeptide oxytocin promotes social affiliative behaviors in a wide range of animals including humans. However, its antiaggressive action has not been unequivocally demonstrated in male laboratory rodents.

Objective: Our primary goal was to examine the putative serenic effect of oxytocin in a feral strain (wild type Groningen, WTG) of rats that generally show a much broader variation and higher levels of intermale aggression than commonly used laboratory strains of rats.

Somatosensory profiles but not numbers of somatosensory abnormalities of neuropathic pain patients correspond with neuropathic pain grading.

Due to the lack of a specific diagnostic tool for neuropathic pain, a grading system to categorize pain as 'definite', 'probable', 'possible' and 'unlikely' neuropathic was proposed. Somatosensory abnormalities are common in neuropathic pain and it has been suggested that a greater number of abnormalities would be present in patients with 'probable' and 'definite' grades. To test this hypothesis, we investigated the presence of somatosensory abnormalities by means of Quantitative Sensory Testing (QST) in patients with a clinical diagnosis of neuropathic pain and correlated the number of sensory abnormalities and sensory profiles to the different grades.

Despite higher glucocorticoid levels and stress responses in female rats, both sexes exhibit similar stress-induced changes in hippocampal neurogenesis.

Sex differences in stress reactivity may be one of the factors underlying the increased sensitivity for the development of psychopathologies in women. Particularly, an increased hypothalamic-pituitary-adrenal (HPA) axis reactivity in females may exacerbate stress-induced changes in neuronal plasticity and neurogenesis, which in turn may contribute to an increased sensitivity to psychopathology. The main aim of the present study was to examine male-female differences in stress-induced changes in different aspects of hippocampal neurogenesis, i.

Fact or factitious? A psychobiological study of authentic and simulated dissociative identity states.

Background: Dissociative identity disorder (DID) is a disputed psychiatric disorder. Research findings and clinical observations suggest that DID involves an authentic mental disorder related to factors such as traumatization and disrupted attachment. A competing view indicates that DID is due to fantasy proneness, suggestibility, suggestion, and role-playing.

Comparison of brain and blood gene expression in an animal model of negative symptoms in schizophrenia.

Objectives: To investigate the potential of white blood cells as probes for central processes we have measured gene expression in both the anterior cingulate cortex and white blood cells using a putative animal model of negative symptoms in schizophrenia.

Methods: The model is based on the capability of ketamine to induce psychotic symptoms in healthy volunteers and to worsen such symptoms in schizophrenic patients. Classical fear conditioning is used to assess emotional processing and cognitive function in animals exposed to sub-chronic ketamine vs.

Bilateral sensory abnormalities in patients with unilateral neuropathic pain; a quantitative sensory testing (QST) study.

In patients who experience unilateral chronic pain, abnormal sensory perception at the non-painful side has been reported. Contralateral sensory changes in these patients have been given little attention, possibly because they are regarded as clinically irrelevant. Still, bilateral sensory changes in these patients could become clinically relevant if they challenge the correct identification of their sensory dysfunction in terms of hyperalgesia and allodynia.

Cost-effectiveness of escitalopram in major depressive disorder in the Dutch health care setting.

Objective: This study assessed the cost-effectiveness of escitalopram for the treatment of depression in the Netherlands from a societal perspective.

Methods: A decision tree model was constructed using decision analytical techniques. Data sources included published literature, clinical trials, official price/tariff lists, national population statistics, and Delphi panel data.

Fighting stigma of mental illness in midsize European countries.

Purpose: Stigma is the most powerful obstacle to the development of mental health care. Numerous activities aiming to reduce the stigma of mental illness and the consequent negative discrimination of the mentally ill and their families have been conducted in Europe. Descriptions of many of these activities are not easily available, either because there are no publications that describe them, or because descriptions exist only in local languages.

Lipocalin 2: novel component of proinflammatory signaling in Alzheimer's disease.

Alzheimer's disease (AD) is associated with an altered immune response, resulting in chronic increased inflammatory cytokine production with a prominent role of TNF-α. TNF-α signals are mediated by two receptors: TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Signaling through TNFR2 is associated with neuroprotection, whereas signaling through TNFR1 is generally proinflammatory and proapoptotic.

The role of indoleamine 2,3-dioxygenase in a mouse model of neuroinflammation-induced depression.

Indoleamine 2,3-dioxygenase (IDO), an enzyme which is activated by pro-inflammatory cytokines, has been suggested as a potential link between neuroinflammatory processes in neurodegenerative diseases (like Alzheimer's disease) and depression. The present study aimed to determine whether neuroinflammation-induced increased IDO levels in the mammalian brain will lead to depressive-like behavior. Neuroinflammation was initiated in mice by a single intracerebroventricular injection of lipopolysaccharide (LPS).

The role of p-glycoprotein in psychiatric disorders: a reliable guard of the brain?

A major component in the protection of the brain against blood-borne toxic influences is the multispecific efflux pump P-glycoprotein. This pump, a 170 kD protein, located at the luminal side of the capillary endothelial cells, has a large capacity and is capable of extruding a wide array of structurally divergent substrates. The brain uptake of the majority of antidepressants and antipsychotics, as well as many other psychotropic drugs and endogenous compounds is hampered by the activity of P-glycoprotein.

Chronic stress and antidepressant agomelatine induce region-specific changes in synapsin I expression in the rat brain.

The antidepressant agomelatine acts as a melatonergic receptor (MT(1)/MT(2)) agonist and 5-HT(2C) receptor antagonist. Agomelatine has demonstrated efficacy in treating depression, but its neurobiological effects merit further investigation. Preclinical studies reported that agomelatine enhances adult hippocampal neurogenesis and increases expression of several neuroplasticity-associated molecules.