Abigail J. Sheldrick

Regulatory T cells increased while IL-1β decreased during antidepressant therapy

BACKGROUND Regulatory T cells (Tregs, CD4(+)CD25(hi)) are specialized in steering the immune response and cytokine release to maintain tolerance to self-antigens. As cytokines such as interleukin (IL)-1β, IL-6 and interferon (IFN)-α have been shown to be involved in the pathophysiology of depression and cytokine levels have been shown to change during successful antidepressant treatment, we tested the involvement CD4(+)CD25(hi) Tregs in these immunological processes during antidepressant therapy. METHODS 16 patients suffering from a depressive episode were included into the study and treated with antidepressants according to their doctors choice. Blood samples were collected during the first week after admission and after 6 weeks of treatment. Therein, we determined plasma levels of IL-1β, and measured IL-1β, IL-6 and IFN-α levels in the stimulated blood by performing a whole blood assay. We distinguished lymphocytes and identified CD4(+)CD25(hi) Tregs by multiparameter flow cytometry. The psychopathological status was assessed using the Hamilton Depression Rating Scale (HAMD-21). RESULTS HAMD-21 score, IL-1β serum levels as well as LPS-stimulated IL-1β and IL-6 production had decreased significantly at the end of treatment. In contrast, the amount of CD4(+)CD25(hi) cells increased significantly from 2.74% ± 0.88 (mean value ± standard deviation) to 3.54% ± 1.21; p = 0.007. No significant changes in virus-induced IFN-α production was observed. CONCLUSIONS The increase in CD4(+)CD25(hi) Tregs during antidepressant therapy may be the reason for the decrease in cytokine production and the recovery from depression.

Impact of antipsychotics on cytokine production in-vitro

OBJECTIVE A growing body of data from genetic, immunological and clinical studies indicates an involvement of the immune system in the pathophysiology of schizophrenia and suggests that the modulation of the cytokine system by antipsychotics may be one cause for the improvement of psychotic symptoms. However, the influence of the typical antipsychotics chlorpromazine and haloperidol, and the effect of typical and atypical antipsychotics on the TSST-1-stimulated blood cell secretion of cytokines, and specifically the interleukin (IL)-17 production have not been studied so far, although IL-17 is a leading pro-inflammatory cytokine. METHOD We measured levels of IL-1β, IL-2, IL-4, IL-6, IL-17 and tumor necrosis factor-α (TNF-α) in stimulated blood of 10 healthy female subjects in a whole blood assay using the toxic shock syndrome toxin TSST-1 as stimulant. Blood was either supplemented with antipsychotics (chlorpromazine, haloperidol, clozapine, N-desmethylclozapine and quetiapine with four different concentrations each) or not. RESULTS Under TSST-1 stimulation, antipsychotics as a group had no influence on IL-1β or IL-6 concentrations but increased IL-4 levels. The most consistent findings were seen regarding IL-17. Mean IL-17 concentrations differed significantly between blood with and without antipsychotic supplements and were increased over all antipsychotics and almost all of the applied antipsychotic concentrations. TNF-α levels were increased by chlorpromazine; N-desmethylclozapine and quetiapine reduced IL-2 production. CONCLUSIONS Antipsychotics might, among other mechanisms, act as such by increasing the production of IL-17.

Effect of COMT val158met genotype on cognition and personality

The gene encoding catechol-O-methyltransferase (COMT), an enzyme which regulates prefrontal cortex dopamine, contains a common functional single nucleotide polymorphism (val158met, rs4680G/A), which accounts for part of the interindividual variance in performance during working memory tasks and also predicts personality traits. We examined the relationship between the val158met polymorphism and cognitive function as well as personality traits in 522 healthy individuals (mean age: 24.75 years, SD=5.84, mean years of education: 15.59, SD=2.65). COMT val158met genotype was related in allele dosage fashion to performance in an executive function test, with the met/met carriers scoring highest. Subjects carrying the met/met genotype also scored higher in the disorganization domain of the SPQ-B personality inventory. Consistent with evidence from previous studies, higher dopamine availability of the met/met genotype enhances prefrontally mediated executive function in healthy individuals. Furthermore, we replicated findings from a recent study whereby the COMT genotype also predicts disorganized personality features.

Increased xanthine oxidase in the thalamus and putamen in depression

A growing body of literature suggests persistent and selective structural changes in the cortico-limbic-thalamic-striatal system in patients with recurrent depressive disorder (DD). Oxidative stress is thought to play a key role in these processes. So far, the main scientific focus has been on antioxidant enzymes in this context. For the first time, this proof of concept study examines the activity of the free radicals producing the enzyme, xanthine oxidase (XO), directly in the cortico-limbic-thalamic-striatal system of patients with recurrent depression. The activity of XO was ascertained in the cortico-limbic-thalamic-striatal regions in post-mortem brain tissue of patients with recurrent depressive episodes and individuals without any neurological or psychiatric history (7/7). We measured the XO activity in following brain areas: hippocampus, regio entorhinalis, thalamus, putamen and caudate nucleus. In this study, we report a significant increase of XO activity in the thalamus and the putamen of patients with depression. Our findings contribute to the growing body of evidence suggesting that oxidative stress plays a pivotal role in certain brain areas in recurrent depressive disorder.

Accessibility, standards and challenges of electroconvulsive therapy in Western industrialized countries: A German example

Abstract Objectives. The aim of the study was to document the present situation of electroconvulsive therapy (ECT) in Germany, compare its handling with regard to other industrialized countries and with regard to a survey 12 years ago. Methods. A questionnaire on the frequency and type of administration of ECT in 2008 was sent electronically to 423 psychiatric hospitals. As needed, up to five reminders were carried out by telephone. On this occasion, the question of whether ECT is administered, could be clarified for each hospital. Results. A total of 43% (183/423) of hospitals declared to administer ECT; 63% (115/183) reported nearly 20,000 treatments. A total incidence of 30,000 treatments performed on 2800 individual patients was estimated. This means that 3.4 patients per 105 inhabitants, 0.4‰ of all depressed patients, and about 1% of depressed inpatients, are treated with ECT in Germany. Conclusions. The frequency of application has increased during the last 12 years by a factor of more than 2.5 in Germany. In Western industrialized countries, numbers vary by a factor of more than 10 amongst the countries with a slow trend of equalization. The mode of implementation and the areas of conflict in which the therapy stands seem to be similar.

Muscarinic antagonist effects on executive control of attention

Acetylcholine plays a major role in mediating attention processes. We investigated the muscarinic antagonist effect of scopolamine on functional neuro-anatomy of attention and cognition. We assessed 12 healthy volunteers while performing the Attention Network Task on 0.4 mg scopolamine and placebo in a single-blind randomized trial in a 1.5 T magnetic resonance scanner. Neurocognitive measures included verbal learning, verbal memory, verbal fluency, trail making, digit span, a continuous performance task and a planning task (Tower of London). When compared to placebo, scopolamine increased reaction times for conflicting stimulus processing, together with decreasing brain activation in the anterior cingulate cortex (a brain region involved in conflict processing) suggestive of a muscarinic antagonist effect on executive control of attention. Contrary to the notion of a predominantly right-hemispheric lateralization of cognitive processes associated with orienting attention, scopolamine reduced brain activity in left superior and left middle frontal brain areas. Our neuropsychological test data revealed a selective effect of scopolamine on verbal learning and memory while other cognitive domains, such as planning and working memory, were unaffected. These findings are consistent with muscarinic modulation of dopaminergic neurotransmission in frontal attention networks when processing conflicting information.

From psychosurgery to neuromodulation: deep brain stimulation for intractable Tourette syndrome.

Tourette syndrome is a neuropsychiatric disorder characterized by motor and vocal tics. It is often associated with depression, obsessive-compulsive symptoms, self-injurious behaviour and attention deficit-hyperactivity disorder (ADHD). In intractable patients, neuromodulation using deep brain stimulation (DBS) has widely replaced psychosurgery. Three different key structures are defined for DBS, the medial portion of the thalamus, the globus pallidus internus and the anterior limb of the internal capsule/nucleus accumbens. This is a comprehensive overview on the effect of DBS on motor and non-motor symptoms using different case series and two larger studies.

Nicotinic antagonist effects on functional attention networks

Cholinergic neurotransmission has been implicated in memory and attention. We investigated the effect of the non-competitive nicotinic antagonist mecamylamine on three components of attention processes (i.e. alerting, orienting and executive control) in 12 healthy male subjects whilst performing the Attention Network Task (ANT) in a magnetic resonance imaging (MRI) scanner. Participants received 15 mg mecamylamine in a single blind and placebo- controlled randomized procedure 90 min prior to obtaining functional MRI data. Our results confirm previous reports of beneficial effects of cueing (alerting and orienting) and detrimental effects of conflict (executive control) on reaction times when performing the ANT. The functional MRI data confirmed distinct neural networks associated with each of the three attention components. Alerting was associated with increased left temporal lobe activation while orienting increased bilateral prefrontal, right precuneus and left caudate activation. Executive control activated anterior cingulate and precuneus. Mecamylamine slowed overall response time and down-regulated brain activation associated with orienting and to some extent brain activation associated with executive control when compared to placebo. These findings are consistent with nicotinic modulation of orienting attention by cueing and executive control when responding to conflicting information. The latter nicotine antagonist effect may be mediated via cholinergic modulation of dopamine neurotransmission in mesolimbic pathways.

COMT genotype and its role on hippocampal-prefrontal regions in declarative memory.

INTRODUCTION Memory dysfunction is a prominent feature in schizophrenia. Impairments of declarative memory have been consistently linked to alterations especially within hippocampal-prefrontal regions. Due to the high heritability of schizophrenia, susceptibility genes and their modulatory impact on the neural correlates on memory are of major relevance. In the present study the influence of the COMT val(158)met status on the neural correlates of declarative memory was investigated in healthy subjects. METHODS From an initial behavioural sample of 522 healthy individuals (Sheldrick et al., 2008), 84 subjects underwent fMRI scanning while performing a memory encoding and a retrieval task. The COMT val(158)met status was determined for the whole sample and correlated with cortical activation within the group of n=84 individuals. RESULTS There were no effects of COMT status on behavioural performance. For declarative memory processing the number of met alleles predicted circumscribed bilateral insula and anterior hippocampus activations during memory encoding as well as less deactivations within the bilateral posterior parahippocampal gyri during memory retrieval. DISCUSSION Although declarative memory performance was unaffected, the neural correlates within hippocampal-prefrontal regions demonstrate a link between COMT val(158)met carrier status and brain areas associated with declarative memory processing. The study contributes to a better understanding of the role that susceptibility genes might play in the aetiology of schizophrenia.

TNF-α and Ghrelin: Opposite Effects on Immune System, Metabolism and Mental Health

Tumor necrosis factor-alpha (TNF-alpha) is a glycoprotein hormone with important functions in inflammation and apoptosis. It plays a significant role as a pro-inflammatory cytokine in the defense against viral, bacterial and parasitic infections and autoimmune disorders. Furthermore, it influences energy homeostasis and has an anorexigenic effect on the hypothalamus. TNF-alpha has also been shown to be involved in the pathogenesis of psychiatric disorders such as depression or narcolepsy. Ghrelin is a peptide hormone which primarily regulates eating behavior through modulation of expression of orexigenic peptides in the hypothalamus. Ghrelin administration increases food intake and body weight, while weight loss in turn increases ghrelin levels. Secondly, it posesses anti-inflammatory properties. It also seems to have an impact on mental health as it is has been suggested to have antidepressant and anxiolytic properties. Therefore, TNF-alpha and ghrelin seem to have opposite effects regarding the hypothalamic regulation of eating behavior, modulation of the immune response and the state of mental health.