Anxiolytic effect of chronic intake of supplemental magnesium chloride in rat.

Evidence suggest that magnesium dietary supplementation has several health benefits including lowering blood pressure, reducing insulin resistance, and improving symptoms of depression, anxiety, and migraine. Here, we aimed to study the effect of chronic magnesium supplementation on anxiety-like behavior in rats by supplementing with magnesium their drinking water for 30 days. Anxiety-like behavior was induced by subcutaneous injection of veratrin 30 min before performing elevated plus maze and open field tests to measure anxiety levels and locomotion, respectively. We quantify the concentration of magnesium in plasma and cerebrospinal fluid. We used diazepam to compare the efficacy of magnesium supplementation as an anxiolytic agent. Our results show that rats supplemented with magnesium had a statistically significant decrease in anxiety levels with not effects on locomotion and a statistically significant increase in concentration of magnesium in plasma and cerebrospinal fluid. However, the anxiolytic effect of magnesium supplementation washes-out in 12 days. We discuss the advantages of using supplemental magnesium as anxiolytic.

The Association Between Biomarkers and Neuropsychiatric Symptoms Across the Alzheimer's Disease Spectrum.

OBJECTIVE: To investigate the relationship between Alzheimer's disease biomarkers and neuropsychiatric symptoms. METHODS: Data from two large cohort studies, the Dutch Parelsnoer Institute - Neurodegenerative Diseases and the Alzheimer's Disease Neuroimaging Initiative was used, including subjects with subjective cognitive decline (N = 650), mild cognitive impairment (N = 887), and Alzheimer's disease dementia (N = 626). Cerebrospinal fluid (CSF) levels of Aß42, t-tau, p-tau, and hippocampal volume were associated with neuropsychiatric symptoms (measured with the Neuropsychiatric Inventory) using multiple logistic regression analyses. The effect of the Mini-Mental State Examination (as proxy for cognitive functioning) on these relationships was assessed with mediation analyses. RESULTS: Alzheimer's disease biomarkers were not associated with depression, agitation, irritability, and sleep disturbances. Lower levels of CSF Aß42, higher levels of t- and p-tau were associated with presence of anxiety. Lower levels of CSF Aß42 and smaller hippocampal volumes were associated with presence of apathy. All associations were mediated by cognitive functioning. CONCLUSION: The association between Alzheimer's disease pathology and anxiety and apathy is partly due to impairment in cognitive functioning.

Leptin, Anxiety Symptoms, and Hypothalamic-Pituitary-Adrenal Axis Activity among Drug-Free, Female Suicide Attempters.

BACKGROUND: Dysregulation of leptin secretion and functioning of the hypothalamic-pituitary-adrenal (HPA) axis may be involved in the pathophysiology of suicide. Preclinical and clinical studies have shown interactions between the HPA axis and leptin. There is also evidence for a negative relationship between leptin and anxiety in humans. However, these possible associations have not been studied in individuals with attempted suicide. OBJECTIVES: To examine the relationship between leptin, HPA axis activity, and anxiety in individuals with a recent suicide attempt. METHOD: Sixty-nine individuals with a recent suicide attempt (n = 37 females; n = 32 males) were recruited and subjected to the Dexamethasone Suppression Test (DST), lumbar puncture, and evaluation with the Comprehensive Psychopathological Rating Scale from which the Brief Scale for Anxiety (BSA) was derived. Leptin was analyzed in cerebrospinal fluid (CSF) and cortisol in serum. Leptin was corrected for body mass index (BMI) by dividing CSF-leptin by BMI (CSF-leptin/BMI). Due to gender-related differences in leptin secretion and HPA axis activity, calculations were made for males and females separately. RESULTS: Significant differences were only found among females; CSF-leptin/BMI levels correlated significantly and negatively with BSA (p < 0.05), pre-DST cortisol, and post-DST serum cortisol at 8 a.m. and 3 p.m. (all p < 0.05). Furthermore, CSF-leptin/BMI was significantly lower in nonsuppressors of dexamethasone as compared to suppressors (p < 0.05). CONCLUSIONS: These findings suggest that in females with a recent suicide attempt, low CSF leptin may be related to symptoms of anxiety and a hyperactive HPA axis.

Negative correlation between cerebrospinal fluid FGF21 levels and BDI scores in male Chinese subjects.

Fibroblast growth factor 21 (FGF21) is an important metabolic regulator of glucose homeostasis and lipid metabolism. Recently, FGF21 has been shown to play a robust neuroprotective role and act as a mediator of the effects of mood stabilizers. In the present study, we measured the concentration of FGF21 in human cerebrospinal fluid (CSF) and investigated the relationship of FGF21 levels with depression and anxiety emotions. Sixty-seven Chinese volunteers were recruited from Beijing Jishuitan Hospital. A significant negative association was found between CSF FGF21 levels and Beck Depression Inventory (BDI) scores in male subjects. Our findings provide evidence of the role of FGF21 in mood regulation.

Negative correlation between CSF zinc level and anxiety in male Chinese subjects.

Zinc is crucial for brain development and psychiatric regulation. In the present study, we investigated the relationship between cerebrospinal fluid (CSF) zinc level and anxiety in a group of male Chinese subjects. Results demonstrated that zinc levels had no considerable interindividual variations, ranging from 8.37 to 16.83µm. Correlation analyses revealed that CSF Zinc levels were positively correlated with education years (r=0.225, p=0.024) and negatively correlated with SAS scores (r=-0.287, p=0.004), but not associated with age or BMI. In conclusion, this present study suggests that CSF zinc level is associated with anxiety.

Cerebrospinal fluid and plasma oxytocin concentrations are positively correlated and negatively predict anxiety in children.

The neuropeptide oxytocin (OXT) exerts anxiolytic and prosocial effects in the central nervous system of rodents. A number of recent studies have attempted to translate these findings by investigating the relationships between peripheral (e.g., blood, urinary and salivary) OXT concentrations and behavioral functioning in humans. Although peripheral samples are easy to obtain in humans, whether peripheral OXT measures are functionally related to central OXT activity remains unclear. To investigate a possible relationship, we quantified OXT concentrations in concomitantly collected cerebrospinal fluid (CSF) and blood samples from child and adult patients undergoing clinically indicated lumbar punctures or other CSF-related procedures. Anxiety scores were obtained in a subset of child participants whose parents completed psychometric assessments. Findings from this study indicate that plasma OXT concentrations significantly and positively predict CSF OXT concentrations (r=0.56, P=0.0064, N=27). Moreover, both plasma (r=-0.92, P=0.0262, N=10) and CSF (r=-0.91, P=0.0335, N=10) OXT concentrations significantly and negatively predicted trait anxiety scores, consistent with the preclinical literature. Importantly, plasma OXT concentrations significantly and positively (r=0.96, P=0.0115, N=10) predicted CSF OXT concentrations in the subset of child participants who provided behavioral data. This study provides the first empirical support for the use of blood measures of OXT as a surrogate for central OXT activity, validated in the context of behavioral functioning. These preliminary findings also suggest that impaired OXT signaling may be a biomarker of anxiety in humans, and a potential target for therapeutic development in individuals with anxiety disorders.

Low IL-8 is associated with anxiety in suicidal patients: genetic variation and decreased protein levels.

OBJECTIVE: Recent studies indicate that inflammation may play a role in the pathophysiology of suicidality. Interleukin-8 (IL-8) is a chemokine that in addition to its function in the immune system also exert neuroprotective properties. The involvement of this chemokine in neuropsychiatric conditions is incompletely known. METHOD: We measured plasma and cerebrospinal fluid (CSF) IL-8, as well as the genotype frequency of a single nucleotide polymorphism (-251A/T, rs4073) in the promoter region of the IL8 gene, in suicide attempters (n=206) and healthy controls (n=578). RESULTS: Plasma and CSF levels of IL-8 were significantly lower in suicide attempters with anxiety than in healthy controls. IL-8 in both plasma and CSF correlated negatively with symptoms of anxiety. Compared with the population-based cohort, the IL-8-251T allele was more prevalent among female suicide attempters. Furthermore, suicide attempters carrying this allele showed more severe anxiety. This correlative study warrants further mechanistic studies on the effects of IL-8 in the central nervous system. CONCLUSION: We suggest that IL-8 might be involved in the biological mechanisms mediating resilience to anxiety. Thus, our findings highlight the chemokine IL-8 as a potential target for future development of anti-anxiety treatments and suicide prevention.

Low neuropeptide Y in cerebrospinal fluid in bipolar patients is associated with previous and prospective suicide attempts.

The attempted and accomplished suicide rates in patients with bipolar disorder are 40-50% and 15-20%, respectively. No biological markers that help predict suicide been identified. Human and experimental animal data indicate that dysregulation of the neuropeptide Y (NPY) system plays a role in depression, anxiety, and posttraumatic stress disorder (PTSD). The aim of this study was to explore if low cerebrospinal fluid (CSF) NPY is associated with (1) past suicide attempts, (2) future suicide attempts, and (3) trait anxiety. Lumbar puncture was performed on 120 clinically stable patients with bipolar disorder enrolled in the St Göran Bipolar Project, where the number of previous suicide attempts was documented. NPY-like immunoreactivity (NPY-LI) was determined in cerebrospinal fluid (CSF). Patients were reexamined one year after the lumbar puncture and suicide attempts were recorded. NPY-LI was significantly lower in patients with a history of suicide attempt than in patients who had not attempted suicide prior to lumbar puncture. Importantly, NPY-LI was markedly lower in patients who made a suicide attempt during the follow-up period compared to patients who did not. Patients who attempted suicide during the follow-up also had markedly lower NPY-LI than those with previous suicide attempts who did not reattempt. Our results suggest that low CSF NPY-LI predicts future suicide attempts. The data are in line with the hypothesis that NPY signaling is altered in affective disorders and states of emotional dysregulation.

Anxiety in major depression and cerebrospinal fluid free gamma-aminobutyric acid.

BACKGROUND: Low gamma-aminobutyric acid (GABA) is implicated in both anxiety and depression pathophysiology. They are often comorbid, but most clinical studies have not examined these relationships separately. We investigated the relationship of cerebrospinal fluid (CSF) free GABA to the anxiety and depression components of a major depressive episode (MDE) and to monoamine systems. METHODS AND MATERIALS: Patients with a DSM-IV major depressive episode (N = 167: 130 major depressive disorder; 37 bipolar disorder) and healthy volunteers (N = 38) had CSF free GABA measured by gas chromatography mass spectroscopy. Monoamine metabolites were assayed by high performance liquid chromatography. Symptomatology was assessed by Hamilton depression rating scale. RESULTS: Psychic anxiety severity increased with age and correlated with lower CSF free GABA, controlling for age. CSF free GABA declined with age but was not related to depression severity. Other monoamine metabolites correlated positively with CSF GABA but not with psychic anxiety or depression severity. CSF free GABA was lower in MDD compared with bipolar disorder and healthy volunteers. GABA levels did not differ based on a suicide attempt history in mood disorders. Recent exposure to benzodiazepines, but not alcohol or past alcoholism, was associated with a statistical trend for more severe anxiety and lower CSF GABA. CONCLUSIONS: Lower CSF GABA may explain increasing severity of psychic anxiety in major depression with increasing age. This relationship is not seen with monoamine metabolites, suggesting treatments targeting the GABAergic system should be evaluated in treatment-resistant anxious major depression and in older patients.

Neuroactive steroid levels are modified in cerebrospinal fluid and plasma of post-finasteride patients showing persistent sexual side effects and anxious/depressive symptomatology.

INTRODUCTION: Observations performed in a subset of subjects treated with finasteride (an inhibitor of the enzyme 5α-reductase) for male pattern hair loss seem to indicate that sexual dysfunction as well as anxious/depressive symptomatology may occur at the end of the treatment and continue after discontinuation. AIM: A possible hypothesis to explain depression symptoms after finasteride treatment might be impairment in the levels of neuroactive steroids. Therefore, neuroactive steroid levels were evaluated in paired plasma and cerebrospinal fluid samples obtained from male patients who received finasteride for the treatment of androgenic alopecia and who, after drug discontinuation, still show long-term sexual side effects as well as anxious/depressive symptomatology. METHODS: The levels of neuroactive steroids were evaluated by liquid chromatography-tandem mass spectrometry in three postfinasteride patients and compared to those of five healthy controls. MAIN OUTCOME MEASURES: Neuroactive steroid levels in plasma and cerebrospinal fluid of postfinasteride patients and healthy controls. RESULTS: At the examination, the three postfinasteride patients reported muscular stiffness, cramps, tremors, and chronic fatigue in the absence of clinical evidence of any muscular disorder or strength reduction. Severity and frequency of the anxious/depressive symptoms were quite variable; overall, all the subjects had a fairly complex and constant neuropsychiatric pattern. Assessment of neuroactive steroid levels in patients showed some interindividual differences. However, the most important finding was the comparison of their neuroactive steroid levels with those of healthy controls. Indeed, decreased levels of tetrahydroprogesterone, isopregnanolone and dihydrotestosterone and increased levels of testosterone and 17ß-estradiol were reported in cerebrospinal fluid of postfinasteride patients. Moreover, decreased levels of dihydroprogesterone and increased levels of 5α-androstane-3α,17ß-diol and 17ß-estradiol were observed in plasma. CONCLUSION: The present observations confirm that an impairment of neuroactive steroid levels, associated with depression symptoms, is still present in androgenic alopecia patients treated with finasteride despite the discontinuation of the treatment.

Behavioural profiles in captive-bred cynomolgus macaques: towards monkey models of mental disorders?

BACKGROUND: To date, experimental and preclinical studies on neuropsychiatric conditions have almost exclusively been performed in experimentally-induced animal models and have only rarely relied upon an ethological approach where animals have been observed in more naturalistic settings. The laboratory species of choice has been the rodent while the potential of more closely-related non-human primates have remained largely underexplored. METHODS: The present study, therefore, aimed at investigating the possible existence of spontaneous atypical/abnormal behaviours displayed by 40 cynomolgus macaques in captive conditions using an unbiased ethological scan-sampling analysis followed by multifactorial correspondence analysis and a hierarchical clustering. RESULTS: The study identified five distinct profiles (groups A to E) that significantly differed on several behaviours, body postures, body orientations, gaze directions and locations in the cage environment. We suggest that animals from the low n groups (D and E) present depressive-like and anxious-like symptoms, reminiscent of depressive and generalized anxiety disorders. Inter-individual differences were highlighted through unbiased ethological observations of spontaneous behaviours and associated parameters, although these were not associated with differences in plasma or cerebrospinal fluid levels of either stress-related hormones or monoamines, i.e. in accordance with the human situation. CONCLUSIONS: No interventional behavioural testing was required to discriminate between 3 typical and 2 atypical ethologically-defined behavioural profiles, reminiscent of certain depressive-like and anxiety-like symptoms. The use of unbiased behavioural observations might, thus, allow the identification of animal models of human mental/behavioural disorders and their most appropriate control groups.

Anxiety is related to Alzheimer cerebrospinal fluid markers in subjects with mild cognitive impairment.

BACKGROUND: Anxiety, apathy and depression are common in subjects with mild cognitive impairment (MCI) and may herald Alzheimer's disease (AD). We investigated whether these symptoms correlated with cerebrospinal fluid (CSF) markers for AD in subjects with MCI. Method Subjects with MCI (n=268) were selected from the 'Development of screening guidelines and criteria for pre-dementia Alzheimer's disease' (DESCRIPA) and Alzheimer's Disease Neuroimaging Initiative (ADNI) studies. We measured amyloid ß(1-42) protein (Aß42) and total tau (t-tau) in CSF. Neuropsychiatric symptoms were measured with the Neuropsychiatric Inventory. RESULTS: Depressive symptoms were reported by 55 subjects (21%), anxiety by 35 subjects (13%) and apathy by 49 subjects (18%). The presence of anxiety was associated with abnormal CSF Aß42 [odds ratio (OR) 2.3, 95% confidence interval (CI) 1.6-3.3] and t-tau (OR 2.6, 95% CI 1.9-3.6) concentrations and with the combination of abnormal concentrations of both Aß42 and t-tau (OR 3.1, 95% CI 2.0-4.7). The presence of agitation and irritability was associated with abnormal concentrations of Aß42 (agitation: OR 1.6, 95% CI 1.1-2.3; irritability: OR 2.2, 95% CI 1.5-3.3). Symptoms of depression and apathy were not related to any of the CSF markers. CONCLUSIONS: In subjects with MCI, symptoms of anxiety, agitation and irritability may reflect underlying AD pathology, whereas symptoms of depression and apathy do not.

Effects of chronic administration of tryptophan with or without concomitant fluoxetine in depression-related and anxiety-like behaviors on adult rat.

Depression and anxiety play an important role in decreasing quality of life worldwide. Since tryptophan is a serotonin precursor and low levels of serotonin seems to be related to depression, the effect of oral tryptophan has been investigated for possible potentiation of the action of antidepressant drugs. We investigated the effects of chronically administered tryptophan (50mg/kg/day, p.o.) with or without concomitant fluoxetine (10mg/kg/day, s.c.) on adult rats regarding depression-related and anxiety-like behaviors. Tryptophan levels in cerebrospinal fluid (CSF) were measured 4h after a single administration of daily dosages of chronic treatments. We found that tryptophan increased depressive-related behavior, but did not alter anxiety-like behavior. However, fluoxetine decreased depression-related behavior and was anxiogenic. Tryptophan with concomitant fluoxetine did not alter anxiety-like behavior. Moreover, our data suggests that the antidepressant effect of fluoxetine was not enhanced by concomitant administration of tryptophan, which could be associated with increased levels of tryptophan in CSF. Further investigations are needed to elucidate the related mechanisms.

Cerebrospinal fluid IL-8 levels reflect symptoms of alexithymia in patients with non-inflammatory neurological disorders.

Several recent findings indicate that various interactions between nervous and immune system are important in the pathophysiology of alexithymia. These findings show that a significant role in developing alexithymia may play proinflammatory cytokines. Recent data also indicate that negative emotions related to depressive symptoms and anxiety are related to disturbed levels of interleukin-8 (IL-8). These findings suggest that IL-8 could present also useful immunological marker related to emotional dysregulation in alexithymia. In the present study we have performed psychometric measurement of alexithymia (TAS-20), depression (BDI-II) and anxiety (SAS), and immunochemical measure of cerebrospinal fluid (CSF) and serum levels of IL-8 in 33 inpatients with non-inflammatory neurological disorders (NIND) (mean age 38.8±12.5). The results show that IL-8 in CSF is significantly correlated with TAS-20 (Spearman R=0.46, p=0.007) and SAS (Spearman R=0.44, p=0.009) but not to BDI-II. The findings of the present study indicate that increased level of IL-8 (in CSF) may be related to symptoms of alexithymia and anxiety in patients with NIND.

Evidence for involvement of central noradrenergic activity in crying proneness.

Crying as a response to emotionally-charged situations varies greatly among individuals, genders, and cultures. Information on the neural systems involved in crying behavior comes mainly from studies of pathological laughing and crying in patients after brain injury. The authors assessed crying proneness (CPR) as expressed by the score on the "crying easily" item of the SCL-90 questionnaire in 65 men and 105 women subjects in whom lumbar puncture was performed for diagnostic reasons. None of the subjects showed pathological laughing or crying. The authors estimated the levels of the main metabolites of noradrenaline (MHPG), serotonin (5-HIAA), and dopamine (HVA) in CSF, and searched for associations to CPR score. Subjects with high CPR showed significantly lower MHPG levels than subjects with low CPR, and no differences in 5-HIAA or HVA levels. Higher frequencies of women were found in the subgroups with high CPR. The "crying easily" score was positively associated with the Interpersonal Sensitivity subscale of the SCL-90 questionnaire in female but not in male subjects, indicating the cultural dimension of crying behavior, while it was not associated with the Depression subscale score. It is suggested that central noradrenergic mechanisms control the threshold for tear production in normal crying behavior.

Lower CSF oxytocin concentrations in women with a history of childhood abuse.

Early-life disruption of the parent-child relationship, for example, in the form of abuse, neglect or loss, dramatically increases risk for psychiatric, as well as certain medical, disorders in adulthood. The neuropeptide oxytocin (OT) plays a seminal role in mediating social affiliation, attachment, social support, maternal behavior and trust, as well as protection against stress and anxiety. We therefore examined central nervous system OT activity after early-life adversity in adult women. We measured OT concentrations in cerebrospinal fluid (CSF) collected from 22 medically healthy women, aged 18-45 years, categorized into those with none-mild versus those with moderate-severe exposure to various forms of childhood abuse or neglect. Exposure to maltreatment was associated with decreased CSF OT concentrations. A particularly strong effect was identified for emotional abuse. There were inverse associations between CSF OT concentrations and the number of exposure categories, the severity and duration of the abuse and current anxiety ratings. If replicated, the association of lower adult CSF OT levels with childhood trauma might indicate that alterations in central OT function may be involved in the adverse outcomes of childhood adversity.

A multicenter study about Neurobiology of Suicidal Behavior: design, development, and preliminary results.

The subproject 1.5 "Neurobiology of Suicidal Behavior" is a multicenter study assessing peripheral parameters of the serotonergic, noradrenergic, and dopaminergic transmitter systems. Additionally, stress hormones and the lipid system as well as inhibitory and excitatory amino acids will be investigated. The different parameters are collected in cerebral spinal fluid (CSF), blood, and saliva. Patients with a depressive spectrum disorder with and without a suicide attempt (during the last three weeks) and being medication free for two weeks are included in the study. So far, 103 patients and controls have been recruited. The design and development of this project as well as interconnections with the others subprojects are described. Preliminary results about the stress hormone system and suicidality are presented.

Cerebrospinal fluid 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in HIV-1 infection.

Reduced level of serotonin (5-hydroxytryptamine, 5-HT) in humans has been associated with a number of mental health and behavioral problems including depression, aggression, violence, sexual dysfunctions, sleep and eating disorders. Even though among HIV-1-infected individuals, prevalence of mental health and behavioral problems are common, their relationship with central nervous system serotonin functions is not clearly understood. This investigation was carried out to study the status of CSF 5-HT in HIV-1+ subjects (n = 21), in the early stage of infection, and HIV-1- control subjects (n = 24). Samples of CSF were obtained by lumbar puncture and were analyzed for 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), using high-performance liquid chromatography equipped with electrochemical detector. Levels of CSF 5-HT were significantly lower in the HIV-1+ group compared to the HIV-1- group. There was no significant difference in the CSF 5-HIAA levels between the two groups. In both groups, however, there was a significant correlation between CSF 5-HT and 5-HIAA. In the HIV-1 + group, although CSF 5-HT level was significantly negatively correlated with serostatus, there was no correlation between either CSF 5-HT or 5-HIAA levels and CD4 cell number or any behavioral measures evaluated in this study, including Beck's Depression Inventory and state/trait anxiety scores. These data suggest that HIV-1 infection affects the CNS 5-HT status with no significant association with measures of depression and anxiety, at least in the early stage of infection.

The relationship between clinical effect and concentrations of temazepam in plasma and cerebrospinal fluid.

The clinical pharmacodynamics of temazepam were investigated in patients who received spinal anaesthesia. Total plasma and cerebrospinal fluid temazepam concentrations were measured and correlated with the clinical effects. Sedation was measured by three separate methods. None, including an aggregated score of all three measures, was correlated closely with either the plasma or the cerebrospinal fluid levels (p = 0.86 and 0.12 respectively). Anxiety was measured before and after premedication. The two scores were correlated but the change in anxiety after premedication did not correlate with either the plasma or the cerebrospinal fluid concentrations (p = 0.11 and 0.45 respectively). Short-term memory was measured before and after premedication. The decline in short-term memory ability was moderately well correlated with both the plasma and the cerebrospinal fluid levels (p = 0.0005 and 0.013 respectively). With temazepam, the variation in sedative and anxiolytic effects between subjects is explained not by differences in pharmacokinetics but rather by differences in the pharmacodynamic response. Because sedative and anxiolytic effects are poorly correlated, but the amnesic effect is well correlated with temazepam concentrations, different sites of action for these effects are suggested.