CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 13, Issue 6, 2014

Despite grief being a universal experience and the increased scientific attention paid to grief and bereavement in recent years, studies that seek to better understand the role of the neurological aspects of grief are still scarce. We found 5 studies that discussed the relationship between the neurological aspects of grief due to the death of a loved one. All studies showed an activation of common areas, i.e., the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), prefrontal cortex (PFC), insula and amygdala. These findings could indicate that there is a group of areas working together and responding to generate the symptomatology of grief. Because grief is a universal experience, it is essential that the necessary and effective support can be provided to those who experience the loss of someone considered important in their lives, and this requires understanding grief’s manifestation, its differential diagnosis in reference to other clinical conditions, mainly psychiatric ones, and adequate forms of intervention and treatment when necessary. Proper understanding and support can help prevent the emergence of more serious health problems.

Suicide is considered a deliberate act initiated and concluded by a person with full knowledge or expectation of a fatal result, and one of the main symptoms of depression. An individual’s conscious and excessive ingestion of a damaging substance is also considered to be an attempted suicide. Despite limited knowledge of caffeine abuse, deaths from overdose of caffeine have been reported in the literature. Thus, this study aims to review the existing literature on caffeine consumption and suicide attempts and deaths, investigating the relation between caffeine consumption and suicide attempts and deaths. We found 24 studies that discuss the relationship between caffeine and suicide. The findings revealed that, despite being an addictive substance and potentially fatal in higher doses, caffeine was still a rare factor in a number of studies concerning its relation with suicide attempts and death. The majority of the research found in this study was of the case study type. Furthermore, the majority of studies focus on the assistance offered to the victim and the procedures undertaken to control the bodily damage created. The existing studies indicate the substance may act as either a direct or an indirect agent in suicide. Therefore, a better understanding of how caffeine may be linked to suicide is crucial for its prevention.

Non-invasive stimulation of the human brain to improve depressive symptoms is increasingly finding its way in clinical settings as a viable form of somatic treatment. Following successful modulation of neural excitability with subsequent antidepressant effects, neural polarization by administrating weak direct currents to the scalp has gained renewed interest. A new wave of basic and clinical studies seems to underscore the potential therapeutic value of direct current stimulation in the treatment of depression. Issues concerning the lack of mechanistic insights into the workings of modifying brain function through neural polarization and how this process translates to its antidepressant properties calls for additional research. The range of its clinical applicability has yet to be established.

Anxiety and depression are pathologies that affect human beings in many aspects of life, including social life, productivity and health. Cannabidiol (CBD) is a constituent non-psychotomimetic of Cannabis sativa with great psychiatric potential, including uses as an antidepressant-like and anxiolytic-like compound. The aim of this study is to review studies of animal models using CBD as an anxiolytic-like and antidepressant-like compound. Studies involving animal models, performing a variety of experiments on the above-mentioned disorders, such as the forced swimming test (FST), elevated plus maze (EPM) and Vogel conflict test (VCT), suggest that CBD exhibited an anti-anxiety and antidepressant effects in animal models discussed. Experiments with CBD demonstrated non-activation of neuroreceptors CB1 and CB2. Most of the studies demonstrated a good interaction between CBD and the 5-HT1A neuro-receptor.

This article considered already existing studies about Deep Brain Stimulation in Mood and Anxiety Disorders. In particular, articles regarding Obsessive-Compulsive Disorder and Major Depression were mostly analyzed, due to the lack of researches about other types of Mood and Anxiety Disorders. We have concentrated on the target areas where Deep Brain Stimulation was most commonly applied, and on the effects this measure had on treatment-refractory patients. The obtained results showed that the stimulation of the: nucleus accumbens, subgenual cingulate cortex and ventral capsule/ventral striatum, has a positive influence on the development of the disorders investigated, sometimes showing the complete remission of the symptoms. Although Deep Brain Stimulation was overall found to be a promising and safe treatment for Mood and Anxiety Disorders, there are not enough studies proving its efficacy in wide samples and in the presence of more complex variables.

Electroencephalography has been used to establish the relationship among cortical activity, exercise and mood, such as asymmetry, absolute and relative power. The purpose of this study was to systematically review the influence of cortical activity on mood state induced by exercise. The Preferred Reporting Items in Systematic reviews and Meta-Analyses was followed in this study. The studies were retrieved from MEDLINE/PubMed, ISI Web of Knowledge and SciELO. Search was conducted in all databases using the following terms: EEG asymmetry, sLORETA, exercise, with affect, mood and emotions. Based on the defined criteria, a total of 727 articles were found in the search conducted in the literature (666 in Pubmed, 54 in ISI Web of Science, 2 in SciELO and 5 in other data sources). Total of 11 studies were selected which properly met the criteria for this review. Nine out of 11 studies used the frontal asymmetry, four used absolute and relative power and one used sLORETA. With regard to changes in cortical activity and mood induced by exercise, six studies attributed this result to different intensities, one to duration, one to type of exercise and one to fitness level. In general, EEG measures showed contradictory evidence of its ability to predict or modulate psychological mood states through exercise intervention.

The observation that nicotine modulates negative affectivity and has a mood enhancing effect mainly derives from studies conducted in the general population and in clinical samples, mostly in nicotine-deprived subjects. It has been explained by the so called deprivation-reversal hypothesis (i.e., nicotine modulates affect because it alleviates withdrawal symptoms). However, experimental studies suggest that nicotine might modulate different affective functions (e.g., aggressiveness, anxiety) and exert a direct modulating effect on human affectivity. The present paper is a systematic review of the literature aiming at verifying this second hypothesis. A computerized search was carried out (PubMed/Medline 1960-2012). Inclusion criteria were: 1. English language papers published in peer-reviewed journals; 2. experimental/quasi experimental design studies; 3. no deprived adults; 4. inclusion of a control condition; 5. no additional Axis I or II psychiatric disorders. Twenty-one papers met our inclusion criteria. Nicotine was showed to alleviate depression both in smokers and non-smokers, especially if depressed or vulnerable to depression. This effect seemed related to the activation of the dopaminergic brain rewarding system. No clear effect on anxiety was found. Nicotine, thus, seems to exert a direct modulating effect on human mood. Possible limitations of the reviewed studies and future research directions are proposed.

Chest pain may be due benign diseases but often suggests an association with coronary artery disease, which justifies a quick search for medical care. However, some people have anxiety disorder with symptoms that resemble clearly an acute coronary syndrome. More specifically, during a panic attack an abrupt feeling of fear accompanied by symptoms such as breathlessness, palpitations and chest pain, makes patients believe they have a heart attack and confuse physicians about the diagnosis. The association between panic disorder and coronary artery disease has been extensively studied in recent years and, although some studies have shown anxiety disorders coexisting or increasing the risk of heart disease, one causal hypothesis is still missing. The aim of this systematic review is to present the various ways in which the scientific community has been investigating the relation between chest pain, panic disorder and coronary artery disease.

Anxiety and depression are the most frequently diagnosed psychological diseases showing a high co-morbidity. They have a severe impact on the lives of the persons concerned. Many meta-analytical studies suggested a positive anxiolytic and depression-reducing effect of exercise programs. The aim of the present article is to synthesize metaanalyses on the effects of exercise on anxiety and depression and to describe average effect sizes. For this purpose 37 meta-analyses were included reporting 50 effect sizes for anxiety scores of 42,264 participants and depression scores of 48,207 persons. The average documented anxiolytic effect of exercise in these reviews was small, 0.34. In contrast, the effect of exercise on depression was significantly higher and at a moderate level, 0.56. Data of randomized controlled trials suggest higher sizes for the effect of exercise on anxiety and depression leading to increases up to moderate and large effects, respectively. Additionally, exercise seems to be more beneficial for patients compared to participants within a non-clinical, normal range of psychological disease. Especially for the effect of exercise on anxiety, more high quality meta-analyses of randomized controlled trials are needed. Finally, possible neurobiological explanations are suggested for the positive effect of exercise on psychological disorders like anxiety and depression.

Both, psychosocial stress and exercise in the past have been used as stressors to elevate saliva cortisol and change state anxiety levels. In the present study, high-school students at the age of 14 were randomly assigned to three experimental groups: (1) an exercise group (n = 18), that was running 15 minutes at a medium intensity level of 65-75% HRmax, (2) a psychosocial stress group (n = 19), and (3) a control group (n = 18). The psychosocial stress was induced to the students by completing a standardized intelligence test under the assumption that their IQ scores would be made public in class. Results display that only psychosocial stress but not exercise was able to significantly increase cortisol levels but decreased cognitive state anxiety in adolescents. The psychosocial stress protocol applied here is proposed for use in future stress studies with children or adolescents in group settings, e.g., in school.

Specific phobia is an anxiety disorder characterized by irrational fear and avoidance of specific things or situations, interfering significantly with the patients’ daily life. Treatment for the disorder consists of both pharmacological and psychological approaches, mainly cognitive behavioral therapy (CBT). Neuroimaging techniques have been used in an attempt to improve our understanding of the neurobiology of SP and of the effects of treatment options available. This review describes the design and results of eight articles investigating the neuroimaging correlates of pharmacological and psychological treatments for SP. The studies show that CBT is effective in SP, leading to a reduction of anxiety symptoms that is accompanied by functional alterations in the brain. The results of pharmacological interventions for SP are less uniform, but suggest that the partial agonist of the NMDA (N-methyl D-aspartate) receptor DCS (D-cycloserine) can be used in combination with psychotherapy techniques for the achievement of quicker treatment response and that DCS modulates the function of structures implicated in the neurobiology of SP. Further research should explore the augmentation of CBT treatment with DCS in controlled trials.

Depression, the most prevalent psychiatric disorder, has a lifelong risk of 20% and is related to high rates of death among the patients. Thus, this study aims to conduct a systematic review of changes in executive functions of adult patients diagnosed with depression. We found 1381 articles; however, only 28 were selected and recovered. The inclusion criteria was the assessment of executive functions with at least one neuropsychological test, and articles that evaluated primarily adult individuals with depression, without comparison to other psychiatric disorders. Although most of the studies (25 out of 28 analyzed) have shown deficits in some executive subcomponents, these findings are not conclusive because they used different parameters of assessment. Moreover, many variables were not controlled, such as the different subtypes of the disorder, the high level of severity, comorbidity and the use of drugs. Most studies showed different deficits in executive functions in depressed patients, but further longitudinal studies are needed in order to confirm these findings.

Behcet's syndrome (BD) is a controversial, chronic, and episodic condition that is autoimmune in origin and causes systemic vasculitis in the arteries and genital veins. BD is consistently associated with depression, with an incidence of 86% upon the first appearance of symptoms and disorders of the disease. However, few studies have looked at depression and other psychiatric disorders, such as anxiety, in the context of comorbidity with BD. The aim of this review is to identify articles that focus on the relation between BD and depression as a comorbidity. The studies found revealed a consistently high incidence of depression in the BD population, even when compared with other chronic pathologies including Rheumatoid Arthritis and Psoriasis, although there was a limitation in the use of scales and other tools for assessment and control of comorbid symptoms, moreover there are no studies linking the drugs used in the BD treatment of each patient and the symptoms present in each case. This review clearly shows the lack of research in which depression scores are analyzed in relation to the medications used by individual patients. Additionally, the use of additional scales is necessary to increase the knowledge about the nature and consequences of depression as comorbidity of BD.

One of the most influential theories has conceived unexpected panic attack (PA) as a primal defensive reaction to threat within the internal milieu of the body. This theory is based on findings suggesting the involvement of dysfunctional respiratory regulation and/or abnormally sensitive central neural network of carbon dioxide (CO2)/hydrogen ion (H+) chemoreception in PA. Thus, unexpected PA may be related to phylogenetically older brain structures, including the brainstem areas, which process basic functions related to the organism’s internal milieu. The brainstem represents a crucial area for homeostatic regulation, including chemoreception and cardio-respiratory control. In addition, the midbrain dorsal periaqueductal gray may be involved in the unconditioned defense reactions to proximal threats, including internal physical stimuli. Our aim was to specifically consider the potential involvement of the brainstem in panic disorder (PD) by a comprehensive review of the available neuroimaging studies. Available data are limited and potentially affected by several limitations. However, preliminary evidence of a role of the brainstem in PD can be found and, secondly, the brainstem serotonergic system seems to be involved in panic modulation with indications of both altered serotonergic receptors and 5-HT transporter bindings. In conclusion, our review suggests that the brainstem may be involved in psychopathology of PD and supports the relevant role of subcortical serotonergic system in panic pathogenesis.

The aim of this review was to summarize the recent evidences regarding the pharmacological treatment of panic disorder (PD). The authors performed a review of the literature regarding the pharmacological treatment of PD since the year 2000. The research done in the last decade brought strong evidences of effectiveness for paroxetine, venlafaxine, sertraline, fluvoxamine, citalopram, fluoxetine, clonazepam, and the relatively novel agent escitalopram. There are evidences indicating that the other new compounds inositol, duloxetine, mirtazapine, milnacipran, and nefazodone have antipanic properties and may be effective compounds in the treatment of PD. The effectiveness of reboxetine and anticonvulsants is a subject of controversy. In addition to selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, benzodiazepines and atypical antipsychotics may be valid alternatives in the treatment of PD. Recent data indicate that augmentation strategies with aripiprazole, olanzapine, pindolol or clonazepam may be effective. D-cycloserine is a promising agent in the augmentation of cognitive behavioral therapy.

Current treatments of depression include psychological, pharmacological and physical approaches. Pharmacological interventions to treat depression have previously focused on modifying dysfunctional neurotransmitter systems. Overall, these treatments have demonstrated an ability to manage major depression but otucomes continue to be poor in many patients, especially those with long term illness or with previous multiple relapses. This may be due to the fact that depression is a systemic and neuroprogressive illness involving multiple biological pathways such as immunological factors. There is substantial evidence that cytokine therapies induce depressive symptoms in clinical populations. The model of cytokine-induced depression has provided important information relative to the risk factors and biological pathways involved in the etiology of depressive symptoms and, most importantly, the identification and knowledge of these factors has allowed new treatment targets to be explored. When an exogenous cytokine such as interferon-alpha is administered, proinflammatory cytokines are activated, leading to alterations in neurotransmission and endocrine pathways and producing neurotoxicity. Several new treatments for depression acting through pathways other than amine neurotransmission have emerged in recent years. The regulation of the inflammatory response, the decrease in the activity of the hypothalamic-pituitary-adrenal axis and the prevention of neurotoxicity are potential targets for new drugs. Though these drugs are mostly at the proof-of-concept stage, some of them have already shown promising results for the treatment of depression.

Panic disorder (PD) is an anxiety disorder that is highly disruptive to the patient’s life and needs new options for effective treatments. In this case report, we present an application of repetitive transcranial magnetic stimulation (rTMS) in a refractory patient resistant to cognitive behavior therapy (CBT) and pharmacotherapy who was treated with a combined protocol of rTMS with a sequential stimulation of right and left dorsolateral prefrontal cortex (DLPFC). The protocol was conducted 3 times per week during 4 weeks, with one month follow-up. The fact that the patient showed improvement suggests that rTMS can be an effective option of treatment.

Depression is the most prevalent psychiatric disorder (16.6%) and is frequently associated with impairments in several areas. Sexual dysfunction (SD) is a prevalent problem with rates ranging from 40-45% in adult women and 20- 30% in adult men. A relationship between depression and sexual dysfunction has been shown in the literature although the mechanisms of this association are not yet clear. Many antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), list sexual dysfunction as a side effect. New drug alternatives with fewer side effects have been proposed, and bupropion is one of them. This study aims to review the literature on bupropion and its impact in sexual function on depressed subjects. Most of the studies have noted that bupropion is not only as effective as other antidepressants but has the advantage of a lower impact on sexual functioning. Some other studies have found that bupropion can even enhance sexual function in certain individuals. Bupropion is also effective, when combined with other antidepressants, in treating emergent sexual dysfunction. Bupropion may be an alternative treatment for depression that does not include the sexual side effects associated with most of the prescribed antidepressants available; however, additional research is required.

In order to gain insight into the ammonia-detoxification mechanisms in the brain and liver tissues, we have investigated the effects of hyperammonemia in rats, in vivo, on the activity levels of a number of ammonia- and glutamate-metabolizing enzymes in mitochondria and the cytosolic fractions of the cerebral cortex, cerebellum, hippocampus, striatum and liver. In general, the ammonia metabolizing enzymes – glutaminase, glutamine synthetase, glutamate dehydrogenase, AMP deaminase, adenosine deaminase, as well as aspartate aminotransferase and alanine aminotransferase – are differentially upregulated in various brain and liver regions of the hyperammonemic rats, indicating that divergent ammonia-detoxification mechanisms are involved in the various brain regions and liver in acute hyperammonemia.

Melatonin is produced and released by the pineal gland in a circadian rhythm. This neurohormone has proven to be an antioxidant and anti-inflammatory molecule able to reduce or mitigate cell damage associated with oxidative stress and inflammation, and this phenomenon underlies neurodegenerative disorders. These facts have drawn attention to this indole, triggering interest in evaluating its changes and in its relationship to the processes indicated, and analyzing its role in the mechanisms involved at the onset and development of neurodegenerative diseases, as well as its therapeutic potential. Multiple sclerosis, the most common cause of non-traumatic disability in young adults, is a chronic neuroinflammatory disease, characterized by demyelination, inflammation, and neuronal and oxidative damage. In its early diagnosis, it often requires a differential screening with other neurodegenerative diseases with similar symptoms, such as Huntington’s disease, an autosomal dominant disorder. The onset of both diseases occurs in the second or third decade of life. On the other hand, cerebral ischemia is a major cause of human disability all over the world. Although a cerebral stroke can occur as the result of different damaging insults, severe ischemia produces the death of neuronal cells within minutes. Changes in melatonin levels have been observed in these processes (Huntington’s disease, multiple sclerosis and cerebral ischemia) as part of their pathogenic features. This review aims to update and discuss the role played by melatonin during neurodegenerative processes, specifically in multiple sclerosis, Huntington’s disease, and cerebral ischemia, and its possible therapeutic use. We also provide readers with an update on the many neuroprotective mechanisms exerted by this neurohormone in the Central Nervous System.