GABAB receptors in addiction and its treatment.

The GABA(B) receptor plays an important role in the control of neurotransmitter release, and experiments using preclinical models have shown that modulation of this receptor can have profound effects on the reward process. This ability to affect the reward process has led to clinical investigations into the possibility that this could be a viable target in the treatment of addiction. Presented here is an overview of a number of studies testing this hypothesis in different drug dependencies.

Elucidation of neurobiology of anxiety disorders in children through pharmacological challenge tests and cortisol measurements: a systematic review.

Anxiety disorders are common both in adults and children. While there have been major advances in understanding the neurobiology of anxiety disorders in adults, progress has been more limited in the elucidation of the mechanisms underlying these disorders in childhood. There is a need to delineate childhood biological models, since anxiety represents a significant clinical problem in children and is a risk factor for the subsequent development of anxiety and depression in adulthood.

GABAergic control of novelty stress-responsive epigenetic and gene expression mechanisms in the rat dentate gyrus.

The activity of dentate gyrus granule neurons is under a strong GABAergic tonic inhibitory control which contributes to the sparse activation pattern of these neurons after environmental stimuli. Previously, we reported that in sparse dentate gyrus neurons such stimuli evoke Ser-10 (S10) phosphorylation and Lys-14 (K14) acetylation in the nucleosomal protein histone H3 (H3S10p-K14ac) resulting in the induction of c-Fos. We hypothesized that GABA is an important modulator of novelty stress-evoked epigenomic mechanisms in rat dentate neurons.

Cytokine levels in euthymic bipolar patients.

Background: The pathophysiology of bipolar disorder is not thoroughly understood. Several studies have investigated the possible role of cytokines in psychiatric disorders, based on their role in neuro-immune modulation; however, findings in studies on bipolar disorder remain limited and contradictory, and most studies have focused on either manic or depressive episodes. These studies suggest that both manic and depressive episodes could be pro-inflammatory states.

Association of the anxiogenic and alerting effects of caffeine with ADORA2A and ADORA1 polymorphisms and habitual level of caffeine consumption.

Caffeine, a widely consumed adenosine A(1) and A(2A) receptor antagonist, is valued as a psychostimulant, but it is also anxiogenic. An association between a variant within the ADORA2A gene (rs5751876) and caffeine-induced anxiety has been reported for individuals who habitually consume little caffeine. This study investigated whether this single nucleotide polymorphism (SNP) might also affect habitual caffeine intake, and whether habitual intake might moderate the anxiogenic effect of caffeine.

Significant decreases in frontal and temporal [11C]-raclopride binding after THC challenge.

Delta9-tetrahydrocannabinol (THC) increases prefrontal cortical dopamine release in animals, but this is yet to be examined in humans. In man, striatal dopamine release can be indexed using [11C]-raclopride positron emission tomography (PET), and recent reports suggest that cortical [11C]-raclopride binding may also be sensitive to dopaminergic challenges. Using an existing dataset we examined whether THC alters [11C]-raclopride binding potential (BP(ND)) in cortical regions.

The administration of psilocybin to healthy, hallucinogen-experienced volunteers in a mock-functional magnetic resonance imaging environment: a preliminary investigation of tolerability.

This study sought to assess the tolerability of intravenously administered psilocybin in healthy, hallucinogen-experienced volunteers in a mock-magnetic resonance imaging environment as a preliminary stage to a controlled investigation using functional magnetic resonance imaging to explore the effects of psilocybin on cerebral blood flow and activity. The present pilot study demonstrated that up to 2 mg of psilocybin delivered as a slow intravenous injection produces short-lived but typical drug effects that are psychologically and physiologically well tolerated. With appropriate care, this study supports the viability of functional magnetic resonance imaging work with psilocybin.

International consensus statement on major depressive disorder.

Because considerable variability exists between countries in the management of major depressive disorder, experts in psychiatry gathered for the International Consensus Group on Depression to outline a universal treatment algorithm for this illness. The experts decided to adapt the existing treatment algorithm developed in Japan and discuss strategies for clinical issues that have been problematic in some countries. Specific recommendations were made by the consensus group for screening for, diagnosing, and treating depression, which include periodically screening all patients for depression, completing a differential diagnosis of depression, referring to a psychiatric specialist if needed, establishing a therapeutic alliance with patients and their families, choosing and optimizing the dose of appropriate antidepressants based on individual patient's needs, and incorporating nonpharmacologic treatment strategies as necessary.

Rationale for, barriers to, and appropriate medication for the long-term treatment of depression.

Antidepressants have proven efficacy in the treatment of acute depressive episodes and the prevention of relapse over the long-term. However, whether due to ignorance about the chronicity of depression, intolerable adverse effects, or an inappropriate fear of dependence, antidepressants are often discontinued after remission or recovery from an acute episode, which frequently leads to relapse or recurrence. This, in turn, increases the risk of subsequent poor treatment response and lifelong depressive chronicity.

Effects of 7.5% CO2 challenge in generalized anxiety disorder.

We have previously developed a putative model of generalized anxiety disorder in healthy volunteers using a 20-minute 7.5% carbon dioxide (CO(2)) inhalation challenge. The aim of this study was to validate the 7.

Antagonist-agonist combinations as therapies for heroin addiction: back to the future?

Psychopharmacology is a powerful approach to the treatment of many psychiatric disorders. In this article I discuss the conceptual and practical issues in relation to the use of mu opioid receptor agonist, antagonist and partial agonist drugs in the treatment of opioid addiction, as this is one therapeutic area where all three types of agents are currently available. The choice of pharmacological agent is largely determined by patient profile, existence of ongoing drug misuse, and the kinetics of the drugs available.

Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis.

Background: The authors have previously reported genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) based on expression of 88 human genes.

Aim: To attempt to reproduce these findings, determine the specificity of this signature to CFS/ME, and test for associations between CFS/ME subtype and infection.

Methods: Expression levels of 88 human genes were determined in blood of 62 new patients with idiopathic CFS/ME (according to Fukuda criteria), six patients with Q-fever-associated CFS/ME from the Birmingham Q-fever outbreak (according to Fukuda criteria), 14 patients with endogenous depression (according to DSM-IV criteria) and 29 normal blood donors.

Searching for perfect sleep: the continuing evolution of GABAA receptor modulators as hypnotics.

The non-benzodiazepine GABA(A) receptor modulators ('Z-drugs') - zaleplon, zolpidem, zopiclone and eszopiclone - have become the accepted treatments for insomnia where they are available. However, recent randomized, placebo-controlled trials suggest that, for these drugs, there may be particular efficacy and tolerability profiles and distinct clinical outcomes in specific patient populations. This is particularly apparent when hypnotic/ selective serotonin reuptake inhibitor co-therapy is used to treat patients with co-morbid insomnia and psychiatric disorders, as patient recovery appears to be accelerated and enhanced by some drugs but not others.

Cyproterone to treat aggressivity in dementia: a clinical case and systematic review.

Aggressivity is a common problem in the management of elderly patients with dementia. Medications currently used to diminish aggressive behaviour in dementia can have problematic side effects. We present a case and systematic review of the current knowledge about the use of cyproterone acetate to treat aggressivity (excluding hypersexuality related behaviours) in dementia.

Harms associated with psychoactive substances: findings of the UK National Drug Survey.

Nutt and colleagues' 'rational' scale to assess the harms of commonly used drugs was based on ratings by a panel of experts. This survey aimed to assess drug users' views of the harms of drugs using the same scale. As users' drug choices are not solely based on harms, we additionally assessed perceived benefits.

Effects of acute tryptophan depletion in serotonin reuptake inhibitor-remitted patients with generalized anxiety disorder.

Background: Serotonergic antidepressants [selective serotonin reuptake inhibitor (SSRI)] are first-line treatments for generalised anxiety disorder (GAD); however, it is not known if synaptic serotonin (5-HT) availability is important for SSRI efficacy. The present study tested the hypothesis that temporary reduction in central 5-HT transmission, through acute tryptophan depletion (ATD), would reverse the therapeutic effect of the SSRIs in GAD patients.

Methods: Twelve patients (six males) with GAD, who showed sustained clinical improvement with SSRI treatment, underwent ATD in a double-blind, placebo-controlled, within-subjects design over 2 days, 1 week apart.

Brain opioid receptor binding in early abstinence from alcohol dependence and relationship to craving: an [11C]diprenorphine PET study.

The importance of the opioid receptor system in substance dependence is increasingly recognised. We used PET with the non-selective tracer [11C]diprenorphine to examine opioid receptor binding in early abstinence from alcohol dependence and the relationship to craving. We recruited 11 alcohol dependent patients and 13 controls.

Equivalent effects of acute tryptophan depletion on REM sleep in ecstasy users and controls.

Introduction: This study sought to test the association between 3,4-methylenedioxymethamphetamine use, serotonergic function and sleep.

Materials And Methods: Ambulatory polysomnography was used to measure three nights sleep in 12 ecstasy users and 12 controls after screening (no intervention), a tryptophan-free amino acid mixture (acute tryptophan depletion (ATD)) and a tryptophan-supplemented control mixture.

Results: ATD significantly decreased rapid eye movement (REM) sleep onset latency, increased the amount of REM sleep and increased the amount of stage 2 sleep in the first 3 h of sleep.

Redistribution of slow wave activity of sleep during pharmacological treatment of depression with paroxetine but not with nefazodone.

It has been suggested that increase in delta sleep ratio (DSR), a marker for the relative distribution of slow wave activity (SWA) over night time, is associated with clinical response to antidepressant treatment. We examined this index and its relationship to rapid eye movement (REM) suppression before and during long-term treatment with nefazodone, which does not suppress REM sleep, and paroxetine which does. The effect of serotonin (5-HT(2A)) receptor blockade on the evolution of SWA during treatment was also investigated.

Antidepressant-induced jitteriness/anxiety syndrome: systematic review.

Background: Early worsening of anxiety, agitation and irritability are thought to be common among people commencing antidepressants, especially for anxiety disorders. This phenomenon, which may be termed jitteriness/anxiety syndrome, is cited as an explanation for early treatment failure and caution in using selective serotonin reuptake inhibitors (SSRIs). However, we believe that it is inconsistently defined and that robust evidence to support the phenomenon is lacking.

Dopamine transporter binding in females with panic disorder may vary with clinical status.

Background: To date the involvement of dopamine system in neurobiology of panic disorder (PD) has been not investigated by imaging studies in humans. In this study, we evaluated the binding potential of dopamine transporter (DAT) in striatum of patients with PD.

Methods: Subjects comprised seven female patients with current PD, seven female PD patients in remission and seven female healthy controls, matched by age.

Identification of an imidazoline binding protein: creatine kinase and an imidazoline-2 binding site.

Drugs that bind to imidazoline binding proteins have major physiological actions. To date, three subtypes of such proteins, I(1), I(2) and I(3), have been proposed, although characterisations of these binding proteins are lacking. I(2) binding sites are found throughout the brain, particularly dense in the arcuate nucleus of the hypothalamus.

Serotonin transporter promoter region polymorphisms do not influence treatment response to escitalopram in patients with major depression.

Several studies and meta-analyses have implicated a polymorphism in the promoter region of the serotonin transporter (5-HTT) gene, 5-HTTLPR in treatment outcomes of selective serotonin re-uptake inhibitors in patients with major depression. In this study we investigated the impact of 5-HTTLPR and a functional SNP rs25531 on the treatment outcomes to escitalopram in depressive patients. The study sample consisted of 135 outpatients with major depressive disorder (mean age 31.