Review Article
Inflammation, insulin resistance and neuroprogression in depression
- Brian E. Leonard, Gregers Wegener
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- Published online by Cambridge University Press:
- 12 June 2019, pp. 1-9
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Chronic low-grade inflammation has been observed in major depression and other major psychiatric disorders and has been implicated in metabolic changes that are commonly associated with these disorders. This raises the possibility that the effects of dysfunctional metabolism may facilitate changes in neuronal structure and function which contribute to neuroprogression. Such changes may have implications for the progress from major depression to dementia in the elderly patient. The purpose of this review is to examine the contribution of inflammation and hypercortisolaemia, which are frequently associated with major depression, to neurodegeneration and how they detrimentally impact on brain energy metabolism. A key factor in these adverse events is insulin insensitivity caused by pro-inflammatory cytokines in association with desensitised glucocorticoid receptors. Identifying the possible metabolic changes initiated by inflammation opens new targets to ameliorate the adverse metabolic changes. This has resulted in the identification of dietary and drug targets which are of interest in the development of a new generation of psychotropic drugs.
Monocyte count in schizophrenia and related disorders: a systematic review and meta-analysis
- Mario Gennaro Mazza, Martina Capellazzi, Sara Lucchi, Ilaria Tagliabue, Aurora Rossetti, Massimo Clerici
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- 17 March 2020, pp. 229-236
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Objective:
Increasing evidence suggests that immunological and inflammatory dysfunctions may play an important role in predisposition, onset, and progression of schizophrenia and related psychosis. The activation of cells of the mononuclear phagocyte system, especially microglia and monocytes, has been reported in schizophrenia. We carried out this systematic review and meta-analysis to investigate if there are significant differences in monocyte count comparing healthy controls with people suffering from schizophrenia and related disorders.
Methods:We searched main electronic databases; nine records met all our criteria and were included in the meta-analysis. Meta-analyses based on random effects models have been carried out generating pooled standardised mean differences (SMDs) of monocyte count in peripheral blood between schizophrenia and related psychosis and healthy controls. Heterogeneity was estimated. Relevant sensitivity and subgroup analyses were conducted.
Results:Patients showed higher monocyte count as compared with healthy control (SMD = 0.393; p = 0.001). Heterogeneity across studies was from moderate to high (I2 = 65.952%); sensitivity analysis leaving out two studies responsible for most of the heterogeneity showed a slightly higher SMD. Subgroup analyses confirmed this result, showing no significant differences in the effect size across different study characteristics.
Conclusions:Monocyte count can be considered an indirect marker of microglia activation in the central nervous system. Thus, the observed higher monocyte count in patients could be considered as a possible peripheral marker of microgliaʼs activation in schizophrenia disorder.
Pharmacological treatments for social anxiety disorder in adults: a systematic review and network meta-analysis
- Taryn Williams, Michael McCaul, Guido Schwarzer, Andrea Cipriani, Dan J Stein, Jonathan Ipser
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- 10 February 2020, pp. 169-176
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Objective:
The aim of this paper was to provide a systematic review and update on the pharmacotherapy of social anxiety disorder (SAD), including the efficacy and tolerability of these agents, the ranking of interventions, and the grading of results by quality of evidence.
Methods:The Common Mental Disorder Controlled Trial Register and two trial registries were searched for randomised controlled trials (RCTs) comparing any pharmacological intervention or placebo in the treatment of SAD. We performed a standard pairwise meta-analysis using a random effects model and carried out a network meta-analysis (NMA) using the statistical package, R. Quality of evidence was also assessed.
Results:We included 67 RCTs in the review and 21 to 45 interventions in the NMA. Paroxetine was most effective in the reduction of symptom severity as compared to placebo. Superior response to treatment was also observed for paroxetine, brofaromine, bromazepam, clonazepam, escitalopram, fluvoxamine, phenelzine, and sertraline. Higher dropout rates were found for fluvoxamine. Brofaromine, escitalopram, fluvoxamine, paroxetine, pregabalin, sertraline, and venlafaxine performed worse in comparison to placebo for the outcome of dropouts due to adverse events. Olanzapine yielded a relatively high rank for treatment efficacy and buspirone the worse rank for dropouts due to any cause.
Conclusion:The differences between drugs and placebo were small, apart from a significant reduction in symptom severity and response for paroxetine. We suggest paroxetine as a first-line treatment of SAD, with the consideration of future research on the drug olanzapine as well as brofaromine, bromazepam, clonazepam, escitalopram, fluvoxamine, phenelzine, and sertraline because we observed a response to treatment.
Systematic review of gene expression studies in people with Lewy body dementia
- Anisa Chowdhury, Anto P. Rajkumar
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- 17 March 2020, pp. 281-292
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Objectives:
Lewy body dementia (LBD) is the second most prevalent neurodegenerative dementia and it causes more morbidity and mortality than Alzheimer’s disease. Several genetic associations of LBD have been reported and their functional implications remain uncertain. Hence, we aimed to do a systematic review of all gene expression studies that investigated people with LBD for improving our understanding of LBD molecular pathology and for facilitating discovery of novel biomarkers and therapeutic targets for LBD.
Methods:We systematically reviewed five online databases (PROSPERO protocol: CRD42017080647) and assessed the functional implications of all reported differentially expressed genes (DEGs) using Ingenuity Pathway Analyses.
Results:We screened 3,809 articles and identified 31 eligible studies. In that, 1,242 statistically significant (p < 0.05) DEGs including 70 microRNAs have been reported in people with LBD. Expression levels of alternatively spliced transcripts of SNCA, SNCB, PRKN, APP, RELA, and ATXN2 significantly differ in LBD. Several mitochondrial genes and genes involved in ubiquitin proteasome system and autophagy–lysosomal pathway were significantly downregulated in LBD. Evidence supporting chronic neuroinflammation in LBD was inconsistent. Our functional analyses highlighted the importance of ribonucleic acid (RNA)-mediated gene silencing, neuregulin signalling, and neurotrophic factors in the molecular pathology of LBD.
Conclusions:α-synuclein aggregation, mitochondrial dysfunction, defects in molecular networks clearing misfolded proteins, and RNA-mediated gene silencing contribute to neurodegeneration in LBD. Larger longitudinal transcriptomic studies investigating biological fluids of people living with LBD are needed for molecular subtyping and staging of LBD. Diagnostic biomarker potential and therapeutic promise of identified DEGs warrant further research.
Gene–environment interactions between HPA-axis genes and childhood maltreatment in depression: a systematic review
- Caroline Normann, Henriette N. Buttenschøn
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- 06 January 2020, pp. 111-121
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Objective:
Gene–environment (GxE) interactions may comprise an important part of the aetiology of depression, and childhood maltreatment (CM), a significant stressor, has consistently been linked to depression. Hence, in this systematic review, we aimed to investigate the interaction between hypothalamus–pituitary–adrenal axis (HPA-axis) genes and CM in depression.
Methods:We conducted a literature search using the Pubmed, Embase, and PsychINFO databases in adherence with the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. We included studies investigating GxE interactions between HPA-axis genes [Angiotensin Converting Enzyme (ACE), Arginine Vasopressin (AVP), Corticotrophin Releasing Hormone (CRH), Corticotrophin Releasing Hormone Receptor 1 (CRHR1), Corticotrophin Releasing Hormone Receptor 2 (CRHR2), FK506 binding protein (FKBP5), Nuclear Receptor subfamily 3 group C member 1 (NR3C1), Nuclear Receptor subfamily 3 group C member 2 (NR3C2)] and CM in depression.
Results:The literature search identified 159 potentially relevant studies. Following screening, 138 of these were excluded. Thus, 21 studies, investigating a total of 51 single nucleotide polymorphisms, were included in the final study. The most prevalent genes in the current study were CRHR1 and FKBP5. Significant GxE interactions were reported in seven of eight studies for CRHR1:rs110402 and CM, and in five of eight studies for FKBP5:rs1360780 and CM. In summary, our results suggest possible GxE interactions between CRHR1, FKBP5, NR3C1, and NR3C2 and CM, respectively. For the remaining genes, no relevant literature emerged.
Conclusions:We find that genetic variation in four HPA-axis genes may influence the effects of CM in depression.
Stimulation-induced side effects after deep brain stimulation – a systematic review
- Marcin Zygmunt Zarzycki, Izabela Domitrz
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- 14 October 2019, pp. 57-64
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Objective:
Deep brain stimulation (DBS) was approved by Food and Drug Administration for Parkinson’s disease, essential tremor, primary generalised or segmental dystonia and obsessive-compulsive disorder (OCD) treatment. The exact mechanism of DBS remains unclear which causes side effects. The aim of this review was to assess variables causing stimulation-induced chronic psychiatric/personality-changing side effects.
Methods:The analysis of scientific database (PubMed, Cochrane Library, EMBASE) was conducted. The included articles had to be research study or case report and DBS to be conducted in therapeutic purposes. The researches with mental disorders in patients’ medical histories were excluded.
Results:Seventeen articles were used in the review. In the group of movement disorders the characteristic of side effects was strongly related to the placement of the electrode implantation. Tiredness/fatigue was correlated with DBS in thalamus. Implantations in subthalamic nucleus were mostly followed by affective side effects such as depression or suicide. The higher voltage of electrode was connected with more severe depression after implantation. The analysis of affective disorder contained only three articles – two about OCD and one about depression. Forgetfulness and word-finding problems as activities connected with cognition may be an inevitable side effect if obsessive thoughts are to be inhibited.
Conclusion:DBS of subthalamic nucleus should be seen as the most hazardous place of implantation. As a result there is a strong need of ‘gold standards’ based on the connectivity research and closer cooperation of scientists and clinicians.
Original Article
Prenatal restraint stress impairs recognition memory in adult male and female offspring
- Clarissa A. Moura, Matheus C. Oliveira, Layse F. Costa, Pamella R. F. Tiago, Victor A. D. Holanda, Ramon H. Lima, Fernanda C. Cagni, Bruno Lobão-Soares, Franscico Bolaños-Jiménez, Elaine C. Gavioli
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- 29 January 2020, pp. 122-127
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Objective:
Accumulating evidence from preclinical and clinical studies indicates that prenatal exposure to stress impairs the development of the offspring brain and facilitates the emergence of mental illness. This study aims to describe the impact of prenatal restraint stress on cognition and exploration to an unfamiliar environment at adulthood in an outbred strain of mice.
Methods:Late pregnant mice were exposed to restraint stress and adult offspring (60 days of age) behaviours were assessed in the object recognition task and open field test.
Findings:Prenatal stress (PNS) impaired new object recognition in male and female mice. Importantly, the learning deficits in female PNS mice were linked to their estrous cycle. Actually, PNS females in metestrus/diestrus but not in proestrus/estrus phases displayed recognition deficits compared to controls. Concerning locomotion in an unfamiliar environment, male but not female PNS mice displayed significant increase, but showed no differences in the distance travelled within the centre zone of the arena.
Conclusion:Present findings support the view that maternal restraint-stress during late pregnancy impairs recognition memory in both male and female offspring, and in females, this cognitive deficit is dependent on the estrous cycle phase. Ultimately, these data reinforce that PNS is an aetiological component of psychiatric disorders associated with memory deficits.
Review Article
Neuroimmunological antibody-mediated encephalitis and implications for diagnosis and therapy in neuropsychiatry
- Joseph E. Marinas, Dmitriy Matveychuk, Serdar M. Dursun, Glen B. Baker
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- Published online by Cambridge University Press:
- 03 December 2019, pp. 177-185
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The past decade has seen a surge of reports and investigations into cases of autoimmune-mediated encephalitis. The increasing recognition of these disorders is especially of relevance to the fields of neurology and psychiatry. Autoimmune encephalitis involves antibodies against synaptic receptors, neuronal cell surface proteins and intracellular targets. These disorders feature prominent symptoms of cognitive impairment and behavioural changes, often associated with the presence of seizures. Early in the clinical course, autoimmune encephalitis may manifest as psychiatric symptoms of psychosis and involve psychiatry as an initial point of contact. Although commonly associated with malignancy, these disorders can present in the absence of an inciting neoplasm. The identification of autoimmune encephalitis is of clinical importance as a large proportion of individuals experience a response to immunotherapy. This review focuses on the current state of knowledge on n-methyl-d-aspartate (NMDA) receptor-associated encephalitis and limbic encephalitis, the latter predominantly involving antibodies against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, the γ-aminobutyric acid (GABA)B receptor and leucine-rich glioma-inactivated 1 (LGI1) protein. In addition, we briefly describe anti-dopamine D2 receptor encephalitis. A summary of the literature will focus on common clinical presentations and course, diagnostic approaches and response to treatment. Since a substantial proportion of patients with autoimmune encephalitis exhibit symptoms of psychosis, the relevance of this disorder to theories of psychosis and schizophrenia will also be discussed.
Original Article
Exploring test batteries for depression- and anxiety-like behaviours in female and male ICR and black Swiss mice
- Lydmila Kazavchinsky, Sofi Dahan, Haim Einat
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- 07 May 2020, pp. 293-302
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Objective and rationale: Animal models are critical for the study of mental disorders and their treatments but are repeatedly criticized for problems with validity and reproducibility. One approach to enhance validity and reproducibility of models is to use test batteries rather than single tests. Yet, a question regarding batteries is whether one can expect a consistent individual behavioural phenotype in mice across tests that can be presumed to be part of the same construct. This study was designed to explore the relationship between the behaviours of mice across tests in some variations of test batteries for depression- and anxiety-like behaviours. Methods: Female and male healthy, intact, and untreated mice from the ICR and black Swiss strains were used in four separate experiments. With some variations, mice were exposed to a battery of behavioural tests representing affective- and anxiety-like behaviours. Data were analysed for differences between sexes and for correlations between behaviours within and across the tests in the battery. Results: No differences were found between the sexes. With very few exceptions, we found correlations within tests (when one test has more than one measure or is repeated) but not across different tests within the battery. Conclusions: The results cast some doubt on the utility of behavioural test batteries to represent different facets of emotional behaviour in healthy intact outbred mice, without any interventions or treatments. Additional studies are designed to explore whether stronger relationship between the tests will appear after manipulations or drug treatments.
Review Article
Mitochondrial calcium uniporter as a potential therapeutic strategy for Alzheimer’s disease
- Anila Venugopal, Mahalaxmi Iyer, Venkatesh Balasubramanian, Balachandar Vellingiri
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- 26 December 2019, pp. 65-71
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Alzheimer’s disease (AD), a neurodegenerative disorder, is the leading cause of dementia in the world whose aetiology is still unclear. AD was always related to ageing though there have been instances where people at an early age also succumb to this disease. With medical advancements, the mortality rate has significantly reduced which also makes people more prone to AD. AD is rare, yet the prominent disease has been widely studied with several hypotheses trying to understand the workings of its onset. The most recent and popular hypothesis in AD is the involvement of mitochondrial dysfunction and calcium homeostasis in the development of the disease though their exact roles are not known. With the sudden advent of the mitochondrial calcium uniporter (MCU), many previously known pathological hallmarks of AD may be better understood. Several studies have shown the effect of excess calcium in mitochondria and the influence of MCU complex in mitochondrial function. In this article, we discuss the possible involvement of MCU in AD by linking the uniporter to mitochondrial dysfunction, calcium homeostasis, reactive oxygen species, neurotransmitters and the hallmarks of AD – amyloid plaque formation and tau tangle formation.
Systematic review of genetic variants associated with cognitive impairment and depressive symptoms in Parkinson’s disease
- Tyrra D’Souza, Anto P. Rajkumar
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- Published online by Cambridge University Press:
- 27 August 2019, pp. 10-22
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Objective:
Cognitive impairment and depression are among the most prevalent and most disabling non-motor symptoms in Parkinson’s disease (PD). The genetic factors that are associated with these symptoms remain uncertain. This systematic review aims to summarise the prevailing evidence from all genetic association studies investigating the genetic variants associated with cognitive impairment and depressive symptoms in people with PD.
Method:A systematic review using five online databases: PubMed, PsycINFO, CINAHL, EMBASE and OpenGrey (PROSPERO protocol: CRD42017067431). We completed the quality assessment using the Q-Genie tool.
Results:2353 articles were screened, and 43 articles were found to be eligible to be included. A meta-analysis of studies investigating LRRK2 rs34637584 confirmed that the minor allele carriers had significantly less cognitive impairment (p = 0.015). Further meta-analyses showed that GBA variants rs76763715 (p < 0.001) and rs421016 (p = 0.001) were significantly associated with more cognitive impairment in people with PD. Minor alleles of GBA variants rs76763715, rs421016, rs387906315 and rs80356773 were associated with more depressive symptoms in PD. Moreover, APOE ε4 allele has been associated with more cognitive impairment in PD. BDNF (rs6265) and CRY1 (rs2287161) variants have been associated with more depressive symptoms in people with PD.
Conclusions:PD carriers of GBA variants are at high risk for cognitive decline and depression. Screening for these variants may facilitate early identification and effective management of these non-motor symptoms. The molecular mechanisms underlying favourable cognitive functioning in LRRK2 rs34637584 variant carriers warrant further investigation.
Original Article
Differentiating depression and ADHD without depression in adults with processing-speed measures
- Klaus Martiny, Niels Peter Nielsen, Elisabeth H. Wiig
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- 27 April 2020, pp. 237-246
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Objective:
We evaluated processing-speed and shift-cost measures in adults with depression or attention-deficit hyperactivity disorder (ADHD) and monitored the effects of treatment. We hypothesised that cognitive-speed and shift-cost measures might differentiate diagnostic groups.
Methods:Colour, form, and colour–form stimuli were used to measure naming times. The shift costs were calculated as colour–form-naming time minus the sum of colour- and form-naming times. Measurements were done at baseline and end point for 42 adults with depression and 42 with ADHD without depression. Patients with depression were treated with transcranial pulsed electromagnetic fields and patients with ADHD with methylphenidate immediate release.
Results:During depression treatment, reductions in naming times were recorded weekly. One-way analysis of variance indicated statistical between-group differences, with effect sizes in the medium range for form and colour–form. In both groups, naming times were longer before than after treatment. For the ADHD group, shift costs exceeded the average–normal range at baseline but were in the average–normal range after stabilisation with stimulant medication. For the depression group, shift costs were in the average–normal range at baseline and after treatment. Baseline colour–form-naming times predicted reductions in naming times for both groups, with the largest effect size and index of forecasting efficiency for the ADHD group.
Conclusions:The cognitive-processing-speed (colour–form) and shift-cost measures before treatment proved most sensitive in differentiating patients with depression and ADHD. Reductions in naming times for the depression group were suggested to reflect improved psychomotor skills rather than improved cognitive control.
Reward sensitivity, affective neuroscience personality, symptoms of attention-deficit/hyperactivity disorder, and TPH2-703G/T (rs4570625) genotype
- Aleksander Pulver, Evelyn Kiive, Jaanus Harro
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- Published online by Cambridge University Press:
- 27 April 2020, pp. 247-256
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Objective:
Reward sensitivity is an increasingly used construct in psychiatry, yet its possible inner structure and relationship with other affective variables are not well known.
Methods:A reward sensitivity measurement scale was constructed on the basis of large item pool collected from birth cohort representative samples (the Estonian Children Personality Behaviour and Health Study; original n = 1238). Affective Neuroscience Personality Scale (ANPS) and the Adult Attention deficit hyperactivity disorder (ADHD) Self-Report Scale (ASRS) were administered in young adulthood. A variant (rs4570625) of the gene encoding tryptophan hydroxylase 2 (TPH2) that is responsible for the synthesis of central serotonin was genotyped.
Results:Reward sensitivity consisted of two orthogonal components, operationally defined as Openness to Rewards and Insatiability by Reward, that respectively characterise the striving towards multiple rewards and the strong pursuit and fixation to a particular reward. While SEEKING and PLAY (and to lower extent CARE) of the ANPS co-varied with Openness to Rewards, FEAR, SADNESS, and ANGER were related to Insatiability by Reward. The total score of ASRS was moderately correlated with Insatiability by Reward, while the association with Openness to Rewards was negligible. However, ASRS Inattention had some negative relationship with the Social Experience facet of Openness to Rewards. The T/T homozygotes for the TPH2 promoter polymorphism had lower Insatiability by Reward but not Openness to Rewards.
Conclusions:Behaviours sensitive to rewards are separable to the components of variability and fixation, and these components are differentially related to affective aspects of personality, attention, and hyperactivity as well as to TPH2 genotype.
Role of d-serine in the beneficial effects of repetitive transcranial magnetic stimulation in post-stroke patients
- Masachika Niimi, Yuko Fujita, Tamaki Ishima, Kenji Hashimoto, Nobuyuki Sasaki, Takatoshi Hara, Naoki Yamada, Masahiro Abo
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- 29 January 2020, pp. 128-134
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Objective:
Abnormalities in neurotransmission via N-methyl-d-aspartic acid receptor (NMDAR) play a role in the pathophysiology of neuropsychiatric disorders. The impact of repetitive transcranial magnetic stimulation (rTMS) on NMDAR-related amino acids remains unknown. We aim to investigate the effects of rTMS on NMDAR-related amino acids in serum of post-stroke patients.
Methods:Ninety-five consecutive post-stroke patients with upper limb hemiparesis were recruited. In 27 patients, the Beck Depression Inventory (BDI) score was 10 or higher. Twelve depressed patients underwent rehabilitation in combination with rTMS and 15 non-depressed patients underwent rehabilitation only without rTMS for 14 days. 1 Hz rTMS was applied to the primary motor area in the non-lesional hemisphere. BDI was conducted before and after treatment. Serum glutamine, glutamate, glycine, l-serine, and d-serine levels were measured before and after treatment.
Results:There were no differences between depressed patients and non-depressed patients in clinical characteristics, levels of the five amino acids in serum, and the ratio of amino acids. However, in 27 depressed patients, there was a significant correlation between levels of glutamate in serum and BDI (ρ = 0.428, p = 0.026). BDI decreased significantly in depressed patients after treatment with or without rTMS. d-serine decreased in the rehabilitation with rTMS group, but increased in the rehabilitation without rTMS group. l-serine increased in the rehabilitation with rTMS group, but decreased in the rehabilitation without rTMS group.
Conclusion:The results suggest that rTMS can modulate NMDAR-related amino acids in blood, producing beneficial effects.
Perspective
How to increase the role of social workers in suicide preventive interventions
- Joshua Levine, Leo Sher
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- 16 March 2020, pp. 186-195
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Objective:
Suicide is a serious public health issue that affects individuals, families and societies all over the world. International studies provide consistent evidence that the presence of psychiatrists in a region is associated with lesser suicide rates. However, many psychiatric patients including suicidal patients do not have access to psychiatrists. This indicates that mental health and non-mental health social workers need to be involved in suicide prevention efforts. This paper is the first comprehensive work that discusses how to increase the role of social workers in the area of suicide prevention.
Methods:A review of the relevant literature.
Results:Increasing the role of social workers in suicide prevention efforts may reduce suicide risk in groups and people at elevated risk for suicide, as well as the general population.
Conclusion:Recommendations are provided for how the social work profession can improve upon suicide prevention while incorporating universal, selective and indicated suicide preventive interventions. Social work research efforts should focus on how to increase the role of social workers in suicide prevention and the management of suicidal patients. Social work education programmes should modify their curricula and increase their attention on suicide prevention. Mental health social workers need to educate the patient and their family on suicide risk factors. Furthermore, mental health and non-mental health social workers need to educate the general public on suicide risk factors.
Original Article
Effect of the monoaminergic stabiliser (−)-OSU6162 on mental fatigue following stroke or traumatic brain injury
- Marie K.L. Nilsson, Birgitta Johansson, Maria L. Carlsson, Robert C. Schuit, Lars Rönnbäck
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- 18 May 2020, pp. 303-312
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The purpose of the present study was to evaluate the efficacy and safety of (−)-OSU6162 in doses up to 30 mg b.i.d. in patients suffering from mental fatigue following stroke or traumatic brain injury (TBI).
Methods:This 4 + 4 weeks double-blind randomised cross-over study included 30 patients afflicted with mental fatigue following a stroke or head trauma occurring at least 12 months earlier. Efficacy was assessed using the Mental Fatigue Scale (MFS), the Self-rating Scale for Affective Syndromes [Comprehensive Psychopathological Rating Scale (CPRS)], the Frenchay Activity Index (FAI), and a battery of neuropsychological tests. Safety was evaluated by recording spontaneously reported adverse events (AEs).
Results:There were significant differences on the patients’ total FAI scores (p = 0.0097), the subscale FAI outdoor scores (p = 0.0243), and on the trail making test (TMT-B) (p = 0.0325) in favour of (−)-OSU6162 treatment. Principal component analysis showed a clear overall positive treatment effect in 10 of 28 patients; those who responded best to treatment had their greatest improvements on the MFS. Reported AEs were mild or moderate in severity and did not differ between the (−)-OSU6162 and the placebo period.
Conclusion:The most obvious beneficial effects of (−)-OSU6162 were on the patients’ activity level, illustrated by the improvement on the FAI scale. Moreover, a subgroup of patients showed substantial improvements on the MFS. Based on these observed therapeutic effects, in conjunction with the good tolerability of (−)-OSU6162, this compound may offer promise for treating at least part of the symptomatology in patients suffering from stroke- or TBI-induced mental fatigue.
Cytokine concentrations are related to level of mental distress in inpatients not using anti-inflammatory drugs
- Helge Toft, Lars Lien, Sudan P. Neupane, Dawit S. Abebe, Terje Tilden, Bruce E. Wampold, Jørgen G. Bramness
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- Published online by Cambridge University Press:
- 30 October 2019, pp. 23-31
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Cross-sectional data show elevated levels of circulating cytokines in psychiatric patients. The literature is divided concerning anti-inflammatory drugs’ ability to relieve symptoms, questioning a causal link between inflammatory pathways and psychiatric conditions. We hypothesised that the development of circulating cytokine levels is related to mental distress, and that this relationship is affected by the use of anti-inflammatory drugs.
Methods:The study was a longitudinal assessment of 12-week inpatient treatment at Modum Bad Psychiatric Center, Norway. Sera and self-reported Global Severity Index (GSI) scores, which measure psychological distress, were collected at admission (T0), halfway (T1) and before discharge (T2). Other variables known to distort the neuroimmune interplay were included. These were age, gender, diagnosis of PTSD, antidepressants and anti-inflammatory drugs. A total of 128 patients (92 women and 36 men) were included, and 28 were using anti-inflammatory medication. Multilevel modelling was used for data analysis.
Results:Patients with higher levels of IL-1RA and MCP-1 had higher GSI scores (p = 0.005 and p = 0.020). PTSD patients scored higher on GSI than non-PTSD patients (p = 0.002). These relationships were mostly present among those not using anti-inflammatory drugs (n = 99), with higher levels of IL-1RA and MCP-1 being related to higher GSI score (p = 0.023 and 0.018, respectively). Again, PTSD patients showed higher GSI levels than non-PTSD patients (p = 0.014).
Conclusions:Cytokine levels were associated with level of mental distress as measured by the GSI scores, but this relationship was not present among those using anti-inflammatory drugs. We found no association between cytokine levels and development of GSI score over time.
Molecular pathway analysis associates alterations in obesity-related genes and antipsychotic-induced weight gain
- Henrik Thyge Corfitsen, Betina Krantz, Agnete Larsen, Antonio Drago
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- 14 November 2019, pp. 72-83
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Objective:
Antipsychotics often induce excessive weight gain. We hypothesised that individuals with genetic variations related to known obesity-risk genes have an increased risk of excessive antipsychotic-induced weight gain (AIWG). This hypothesis was tested in a subset of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) trial data set.
Methods:The CATIE trial compared effects and side effects of five different antipsychotics through an 18-month period. Based on the maximum weight gain recorded, excessive weight gain was defined as >7% weight gain. Cytoscape and GeneMANIA were instrumental in composing a molecular pathway from eight selected genes linked to obesity. Genetic information on a total of 495.172 single-nucleotide polymorphisms (SNPs) were available from 765 (556 males) individuals. Enrichment test was conducted through ReactomePA and Bioconductor. A permutation test was performed, testing the generated pathway against 105 permutated pathways (p ≤ 0.05). In addition, a standard genome-wide association study (GWAS) analysis was performed.
Result:GWAS analysis did not detect significant differences related to excessive weight gain. The pathway generated contained 28 genes. A total of 2067 SNPs were significantly expressed (p < 0.01) within this pathway when comparing excessive weight gainers to the rest of the sample. Affected genes including PPARG and PCSK1 were not previously related to treatment-induced weight gain.
Conclusions:The molecular pathway composed from high-risk obesity genes was shown to overlap with genetics of patients who gained >7% weight gain during the CATIE trial. This suggests that genes related to obesity compose a pathway of increased risk of excessive AIWG. Further independent analyses are warranted that may confirm or clarify the possible reasoning behind.
Anti-HIV drugs promote β-amyloid deposition and impair learning and memory in BALB/c mice
- S.S. Zulu, O. Abboussi, N. Simola, M.V. Mabandla, W.M.U. Daniels
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- 07 May 2020, pp. 257-264
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Objectives:
Growing evidence suggested that antiretroviral (ARV) drugs may promote amyloid beta (Aβ) accumulation in HIV-1-infected brain and the persistence of HIV-associated neurocognitive disorders (HANDs). It has also been shown that lipid peroxidation upregulates β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) expression and subsequently promotes Aβ peptide production. In the present study, we examined whether chronic exposure to the anti-HIV drugs tenofovir disoproxil fumarate (TDF) and nevirapine induces lipid peroxidation thereby promoting BACE1 and Aβ generation and consequently impair cognitive function in mice.
Methods:TDF or nevirapine was orally administered to female BALB/c mice once a day for 8 weeks. On the 7th week of treatment, spatial learning and memory were assessed using the Morris water maze test. The levels of lipid peroxidation, BACE1, amyloid β 1-42 (Aβ1-42) and Aβ deposits were measured in the hippocampal tissue upon completion of treatment.
Results:Chronic administration of nevirapine induced spatial learning and memory impairment in the Morris water maze test, whereas TDF did not have an effect. TDF and nevirapine administration increased hippocampal lipid peroxidation and Aβ1-42 concentration. Nevirapine further upregulated BACE1 expression and Aβ deposits.
Conclusion:Our results suggest that chronic exposure to TDF and nevirapine contributes to hippocampal lipid peroxidation and Aβ accumulation, respectively, as well as spatial learning and memory deficits in mice even in the absence of HIV infection. These findings further support a possible link between ARV drug toxicity, Aβ accumulation and the persistence of HANDs.
Dorsolateral and ventrolateral prefrontal cortex structural changes relative to suicidal ideation in patients with depression
- Ran Zhang, Shengnan Wei, Miao Chang, Xiaowei Jiang, Yanqing Tang, Fei Wang
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- Published online by Cambridge University Press:
- 09 January 2020, pp. 84-91
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The prefrontal cortex (PFC) is enormously important in suicide and major depressive disorder (MDD). However, little is known about the structural alterations in the brains of people with MDD and suicidal ideation. We examined the gray matter volume (GMV) of the PFC of individuals with MDD and suicidal ideation to determine if PFC volumetric differences contribute to suicidal ideation in patients with MDD. Thirty-five subjects with MDD and suicidal ideation, 38 subjects with MDD but without suicidal ideation, and 43 age- and gender-matched healthy control (HC) subjects underwent T1-weighted imaging. A voxel-based morphometric analysis was conducted to compare the PFC GMVs of the three groups. Further GMV reductions in the left and right dorsolateral PFC (DLPFC) and right ventrolateral PFC (VLPFC) were detected in the MDD with suicidal ideation group compared with those in the HC group and the MDD without suicidal ideation group, whereas the MDD without suicidal ideation group only exhibited significant differences in the left DLPFC relative to the HC group. Our findings demonstrated that left DLPFC reductions were associated with MDD and suicidal ideation, and diminished GMV reductions in the right DLPFC and right VLPFC were only associated with suicidal ideation. These results help us better understand the neuropathological changes in MDD with suicidal ideation.