The field of non-invasive stimulation of the cerebellum is quickly expanding. The anatomical structure of the cerebellum with a high density of neurons in the superficial layer, its electrical properties, and its participation in numerous closed-loop circuits involved in motor, cognitive, and affective operations both in children and in adults make of the cerebellum a target with very high potential for neuromodulation of both cerebellar and extra-cerebellar disorders, in neurology, psychiatry, and neurosurgery. A common research effort is required to extract the optimal parameters of stimulation and to identify how non-invasive stimulation of the cerebellum modifies cerebellar plasticity and functional connectivity in remote cortical and subcortical areas. A patient stratification should be considered.

ContextChronic systemic inflammation in obesity originates from local immune responses in visceral adipose tissue. However, assessment of a broad range of inflammation-mediating cytokines and their relationship to physical activity and adipometrics has scarcely been reported to date.ObjectiveTo characterize the profile of a broad range of pro- and anti-inflammatory cytokines and the impact of physical activity and energy expenditure in individuals with general obesity, central obesity, and non-obese subjects.Design, Setting, and ParticipantsA cross-sectional study comprising 117 obese patients (body mass index (BMI) ≥ 30) and 83 non-obese community-based volunteers.Main Outcomes MeasuresSerum levels of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ and tumor necrosis factor (TNF)-α were measured. Physical activity and energy expenditure (MET) were assessed with actigraphy. Adipometrics comprised BMI, weight, abdominal-, waist- and hip-circumference, waist to hip ratio (WHR), and waist-to-height-ratio (WHtR).ResultsGeneral obesity was associated with significantly elevated levels of IL-5, IL-10, IL-12, IL-13, IFN-γ and TNF-α, central obesity with significantly elevated IL-5, IL-10, IL-12, IL-13 and IFN-γ-levels. In participants with general obesity, levels of IL-4, IL-10 and IL-13 were significantly elevated in participants with low physical activity, even when controlled for BMI which was negatively associated with physical acitivity. Cytokines significantly correlated with adipometrics, particularly in obese participants.ConclusionsResults confirm up-regulation of certain pro- and anti-inflammatory cytokines in obesity. In obese subjects, physical activity may lower levels and thus reduce pro-inflammatory effects of cytokines that may link obesity, insulin resistance and diabetes.

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The frequently observed co-occurrence of depressive disorders and inflammatory diseases suggests a close connection between the nervous and the immune systems. Increased pro-inflammatory and type 1 cytokines, such as interleukin (IL)-1, tumour necrosis factor (TNF)-α and interferon (IFN)-γ, appear to be an important link. Cytokines are synthesized by immune cells in the blood and peripheral tissues and by glial cells in the central nervous system (CNS). Evidence suggests that the blood-brain barrier (BBB) is permeable to cytokines and immune cells, and that afferent nerves, e.g. the vagus nerve, mediate the communication between peripheral inflammatory processes and CNS. Cytokines such as IL-1ß, TNF-α and IFN-γ seem to contribute to the pathophysiology of depression by activating monoamine reuptake, stimulating the hypothalamic-pituitary-adrenocortical (HPA) axis and decreasing production of serotonin due to increased activity of indolamine-2,3-dioxygenase (IDO). However, critical appraisal of these hypotheses is required, because cytokine elevation is not specific to depression. Moreover, several effective antidepressants such as amitriptyline and mirtazapine have been shown to increase cytokine production. When applying immunomodulatory therapies, these drugs may increase the risk of specific side effects such as infections or interact with antidepressant drugs on important functions of the body such as the coagulation system.

Our findings suggest that psychiatry has an image problem that is widespread, reflecting community perceptions and the specialist interests of medical students on recruitment. If psychiatry is to improve its 'attractiveness' as a career option, identified image problems need to be corrected and medical student selection processes re-considered.

BackgroundThe ketogenic diet (KD) has been used in treatment-resistant epilepsy since the 1920s. It has been researched in a variety of neurological conditions in both animal models and human trials. The aim of this review is to clarify the potential role of KD in psychiatry.MethodsNarrative review of electronic databases PubMED, PsychINFO, and Scopus.ResultsThe search yielded 15 studies that related the use of KD in mental disorders including anxiety, depression, bipolar disorder, schizophrenia, autism spectrum disorder (ASD), and attention deficit hyperactivity disorder (ADHD). These studies comprised nine animal models, four case studies, and two open-label studies in humans. In anxiety, exogenous ketone supplementation reduced anxiety-related behaviors in a rat model. In depression, KD significantly reduced depression-like behaviors in rat and mice models in two controlled studies. In bipolar disorder, one case study reported a reduction in symptomatology, while a second case study reported no improvement. In schizophrenia, an open-label study in female patients (n = 10) reported reduced symptoms after 2 weeks of KD, a single case study reported no improvement. In a brief report, 3 weeks of KD in a mouse model normalized pathological behaviors. In ASD, an open-label study in children (n = 30) reported no significant improvement; one case study reported a pronounced and sustained response to KD. In ASD, in four controlled animal studies, KD significantly reduced ASD-related behaviors in mice and rats. In ADHD, in one controlled trial of KD in dogs with comorbid epilepsy, both conditions significantly improved.ConclusionDespite its long history in neurology, the role of KD in mental disorders is unclear. Half of the published studies are based on animal models of mental disorders with limited generalizability to the analog conditions in humans. The review lists some major limitations including the lack of measuring ketone levels in four studies and the issue of compliance to the rigid diet in humans. Currently, there is insufficient evidence for the use of KD in mental disorders, and it is not a recommended treatment option. Future research should include long-term, prospective, randomized, placebo-controlled crossover dietary trials to examine the effect of KD in various mental disorders.

Weight gain and metabolic disturbances are common side effects during psychopharmacological treatment with specific antipsychotics and antidepressants. The antipsychotics clozapine and olanzapine, and antidepressants tricyclics and mirtazapine have a high risk of inducing weight gain. Recently discovered pathophysiological mechanisms include antihistaminergic effects, activation of hypothalamic adenosine monophosphate-activated protein kinase (AMPK), modulation of hormonal signaling of ghrelin and leptin, changes in the production of cytokines such as tumor necrosis factor-alpha (TNF)-alpha and adipokines such as adiponektin, and the impact of genes, in particular the melanocortin 4 receptor (MC4R), serotonin 2C receptor (HTR2C), leptin, neuropeptide Y (NPY) and cannabinoid receptor 1 (CNR1) genes. Metabolic changes associated with weight gain include disturbances of glucose and lipid metabolism. Clozapine and olanzapine may, in addition to mechanisms resulting from weight gain, impair glucose metabolism by blockade of the muscarinic M3 receptor (M3R). Antidepressants associated with weight gain appear to have fewer unfavourable effects on glucose and lipid metabolism than the second-generation antipsychotics clozapine and olanzapine. To assess the risk of weight gain and its consequences for the patient's health, assessing body weight changes and metabolic monitoring in the first week of treatment as well as in long-term treatment is recommended.

The interplay between immune and nervous systems plays a pivotal role in the pathophysiology of depression. In depressive episodes, patients show increased production of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α. There is limited information on the effect of antidepressant drugs on cytokines, most studies report on a limited sample of cytokines and none have reported effects on IL-22. We systematically investigated the effect of three antidepressant drugs, citalopram, escitalopram and mirtazapine, on secretion of cytokines IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in a whole blood assay in vitro, using murine anti-human CD3 monoclonal antibody OKT3, and 5C3 monoclonal antibody against CD40, to stimulate T and B cells respectively. Citalopram increased production of IL-1β, IL-6, TNF-α and IL-22. Mirtazapine increased IL-1β, TNF-α and IL-22. Escitalopram decreased IL-17 levels. The influence of antidepressants on IL-2 and IL-4 levels was not significant for all three drugs. Compared to escitalopram, citalopram led to higher levels of IL-1β, IL-6, IL-17 and IL-22; and mirtazapine to higher levels of IL-1β, IL-17, IL-22 and TNF-α. Mirtazapine and citalopram increased IL-22 production. The differing profile of cytokine production may relate to differences in therapeutic effects, risk of relapse and side effects.