Neuroinflammatory Biomarkers in Cerebrospinal Fluid From 106 Patients With Recent-Onset Depression Compared With 106 Individually Matched Healthy Control Subjects.

BACKGROUND: Neuroinflammation has been linked to depression; however, neuroinflammatory biomarkers in the cerebrospinal fluid (CSF) have not previously been thoroughly investigated in a large group of patients with recent-onset depression compared with healthy control subjects. METHODS: We conducted an individually matched case-control study comparing patients with recent-onset depression (ICD-10: F32) to control subjects. Primary outcomes were CSF white cell count (WCC), CSF-to-serum albumin ratio, CSF total protein, and immunoglobulin G (IgG) index. Secondary outcomes were CSF WCC differential count and CSF neutrophil-to-lymphocyte, CSF-to-serum IgG, and CSF-to-plasma glucose ratios. Linear models adjusting for sex and age were applied. RESULTS: We included 106 patients with recent-onset depression (84.0% outpatients) and 106 healthy control subjects. Patients had 18% higher CSF WCC relative to control subjects (relative mean difference [MD]: 1.18; 95% CI: 1.02-1.40; p = .025). CSF WCC differed with depression symptomatology (p = .034), and patients with severe depression (n = 29) had 43% higher CSF WCC relative to control subjects (MD: 1.43; 95% CI: 1.13-1.80, p = .003). Two (1.9%) patients and no controls (0.0%) had CSF WCC above the normal range (>5 × 106/L). No significant differences between groups were observed regarding CSF-to-serum albumin ratio (MD: 1.07; 95% CI: 0.97-1.18; p = .191), CSF total protein (MD: 1.01; 95% CI: 0.94-1.09; p = .775), or IgG index (MD: 1.05; 95% CI: 0.97-1.15; p = .235). Regarding secondary outcomes, the proportion of CSF neutrophils was lower among patients (MD: 0.22; 95% CI: 0.08-0.59; p = .003) relative to control subjects, whereas the remaining outcomes were not significantly different (all p > .06). CONCLUSIONS: Patients had higher CSF WCC relative to control subjects, indicating increased neuroimmunologic activation, particularly for severe depression.

Sex difference in cerebrospinal fluid/blood albumin quotients in patients with schizophreniform and affective psychosis.

BACKGROUND: The importance of cerebrospinal fluid (CSF) diagnostics for psychiatry is growing. The CSF/blood albumin quotient (QAlb) is considered to be a measure of the blood-CSF barrier function. Recently, systematically higher QAlb in males than in females was described in neurological patients. The aim of this study was to investigate whether a sex difference could also be detected in a well-characterized psychiatric cohort. METHODS: The patient cohort comprised 989 patients, including 545 females and 444 males with schizophreniform and affective syndromes who underwent CSF diagnostics, including QAlb measurement. The basic CSF findings and antineuronal autoantibody data of this cohort have already been published. This re-analysis employed analysis of covariance with age correction for QAlb mean values and chi2-testing for the number of increased age-corrected QAlb levels to investigate sex differences in QAlb. RESULTS: The QAlb levels were elevated above reference levels by 18% across all patients, and a comparison between male and female patients revealed a statistically significant sex difference, with increased values in 26% of male patients and a corresponding rate of only 10% in female patients (chi2 = 42.625, p < 0.001). The mean QAlb values were also significantly higher in males (6.52 ± 3.69 × 10-3) than in females (5.23 ± 2.56 × 10-3; F = 52.837, p < 0.001). DISCUSSION: The main finding of this study was a significantly higher QAlb level in male compared to female patients with psychiatric disorders, complementing previously described sex differences in neurological patient cohorts. This result indicates bias from some general factors associated with sex and could be partly explained by sex differences in body height, which is associated with spine length and thus a longer distance for CSF flow within the subarachnoid space down the spine from the occipital area to the lumbar puncture site in males compared to females. Hormonal influences caused by different estrogen levels and other sex-specific factors could also play a relevant role. The significance of the study is limited by its retrospective design, absence of a healthy control group, and unavailability of exact measures of spine length.

On the conundrum of cognitive impairment due to depressive disorder in older patients.

OBJECTIVES: Depressive symptoms and cognitive impairment often concur in older persons. Differentiating the cause of cognitive impairment in older persons with Depressive Disorder (DD) from other diseases such as Alzheimer's Disease (AD) is challenging. The goal of this study was to characterize cognitive impairment in older persons with DD. DESIGN: Cross-sectional retrospective observational clinical cohort study using patient records from 2014 to 2018. SETTING: Gerontopsychiatric services of Ulm University at Bezirkskrankenhaus Günzburg serving as primary psychiatric care institution and tertiary referral center for psychiatric care for older persons. PARTCIPANTS: DD was diagnosed according to ICD-10 criteria. When indicated by the medical history or neuropsychological assessment further diagnostic procedures were initiated. Cerebrospinal fluid (CSF) tap was routinely the first additional procedure. If patients did not consent to CSF tap or contraindications were present, 18F-fluordesoxyglucose-PET (FDG-PET) or Amyloid-PET (Am-PET) were performed. MATERIALS AND METHODS: Extensive neuropsychological test battery to assess cognitive profile. RESULTS: 457 subjects were diagnosed with DD (DD-all; age 50-94; 159 males, 298 females). Biomarkers were assessed in 176 persons; in 90 of these subjects AD-biomarkers were negative (DD-BM-; age 54-89; 40 males, 50 females), and in 86 subjects at least one biomarker was compatible with AD (DD-BM+; age 60-90; 31 males, 55 females). Cognitive performance was below healthy controls (HC; n = 56; age 50-80; 30 males, 26 females) for all groups of patients with DD. With case-control matching of HC and DD-BM- we find that executive functions are impaired in about one out of three and delayed recall in about two out of three patients with DD. CONCLUSION: Cognitive impairment is frequent in older persons with DD. Cognitive profile in older patients with DD without and with biomarkers of AD is not distinguishable. Therefore, cognitive impairment due to DD should be diagnosed after exclusion of comorbid AD.

Preliminary validation of natural depression in macaques with acute treatments of the fast-acting antidepressant ketamine.

Non-human primates have become one of the most important model animals for the investigation of brain diseases because they share a wide-range of genetics and social similarities with human beings. Naturally-evoked depression models in macaques may offer a full spectrum of similarity to human depression states, but they require validation and corroboration of specific phenotypes to depression-associated states before they can be used in research into more effective interventions. It is reported here that depressed cynomolgus monkeys developed in the natural condition display higher levels of typical depressive-like huddling behavior than healthy monkeys. Moreover, these depressed macaques presented other key phenotypes linked to depression, including low levels of cerebrospinal fluid monoamine neurotransmitters and their metabolites, increased passive states, reduced positive behaviors and disrupted nocturnal sleep. When subjected to an acute subanesthetic dose of ketamine, the depressed monkeys responded substantially in rapid and sustained antidepressant-like ways, which demonstrated decreased huddling behavior, an elevated interest in exploration activities and sleep improvement. Taken together, this naturally-evoked depression monkey model was systematically validated for ecological, face, construct and predictive validities. This model will serve as a qualified platform for studying depression in the future.

Depression and Alzheimer's Disease Biomarkers Predict Driving Decline.

BACKGROUND: Symptomatic Alzheimer's disease (AD) and depression independently increase crash risk. Additionally, depression is both a risk factor for and a consequence of AD. OBJECTIVE: To examine whether a depression diagnosis, antidepressant use, and preclinical AD are associated with driving decline among cognitively normal older adults. METHODS: Cognitively normal participants, age ≥65, were enrolled. Cox proportional hazards models evaluated whether a depression diagnosis, depressive symptoms (Geriatric Depression Scale), antidepressant use, cerebrospinal fluid (amyloid-ß42 [Aß42], tau, phosphorylated tau181 [ptau181]), and amyloid imaging biomarkers (Pittsburgh Compound B and Florbetapir) were associated with time to receiving a rating of marginal/fail on a road test. Age was adjusted for in all models. RESULTS: Data were available from 131 participants with age ranging from 65.4 to 88.2 years and mean follow up of 2.4 years (SD = 1.0). A depression diagnosis was associated with a faster time to receiving a marginal/fail rating on a road test and antidepressant use (p = 0.024, HR = 2.62). Depression diagnosis and CSF and amyloid PET imaging biomarkers were associated with driving performance on the road test (p≤0.05, HR = 2.51-3.15). In the CSF ptau181 model, depression diagnosis (p = 0.031, HR = 2.51) and antidepressant use (p = 0.037, HR = 2.50) were statistically significant predictors. There were no interaction effects between depression diagnosis, antidepressant use, and biomarker groups. Depressive symptomology was not a statistically significant predictor of driving performance. CONCLUSIONS: While, as previously shown, preclinical AD alone predicts a faster time to receiving a marginal/fail rating, these results suggest that also having a diagnosis of depression accelerates the onset of driving problems in cognitively normal older adults.

CSF glutamate level decreases in heavy smokers and negatively correlates with BDI scores.

Glutamate is involved in mental disorders and nicotine addiction. The aim of the present study was to evaluate the relationship between cerebrospinal fluid (CSF) glutamate levels and mental status in Chinese heavy smokers. Participants comprised 41 non-smokers and 77 heavy smokers (n = 118). Cerebrospinal fluid was extracted and glutamate levels were measured. We recorded age, years of education, BMI, the Barratt impulsiveness scale (BIS), the Beck Depression Inventory (BDI) and the Self-Rating Anxiety Scale (SAS). BIS action scores, total scores and BDI scores were significantly different between the groups. Partial correlation analyses with age and education years as covariates found that CSF glutamate levels negatively correlated with BDI scores, but did not correlate with SAS scores in heavy smokers. No correlation was found between CSF glutamate levels and BDI or SAS scores in non-smokers. In conclusion, heavy smokers had more impulsivity had lower levels of CSF glutamate and higher BDI scores. CSF glutamate levels negatively correlated with BDI scores in heavy smokers.

Chronic depressive symptomatology and CSF amyloid beta and tau levels in mild cognitive impairment.

OBJECTIVES: To investigate the association between chronic subsyndromal symptoms of depression (SSD), cerebrospinal fluid (CSF) biomarkers, and neuropsychological performance in individuals with mild cognitive impairment (MCI). METHODS: Participants included 238 older adults diagnosed with MCI from the Alzheimer's Disease Neuroimaging Initiative repository with cognitive and CSF amyloid beta (Aß1-42 ), total tau (t-tau), and phosphorylated tau (p-tau) data. The Neuropsychiatric Inventory identified individuals with chronic endorsement (SSD group N = 80) or no endorsement (non-SSD group N = 158) of depressive symptoms across timepoints. CSF biomarker and cognitive performance were evaluated with linear regression models adjusting for age, education, gender, APOE genotype, global cognitive status, and SSD group. RESULTS: As compared to the non-SSD group, the SSD group displayed lower CSF Aß1-42 levels (ß = -24.293, S.E. = 6.345, P < 0.001). No group differences were observed for CSF t-tau (P = 0.497) or p-tau levels (P = 0.392). Lower CSF Aß1-42 levels were associated with poorer performance on learning (ß = 0.041, S.E. = 0.018, P = 0.021) and memory (ß = -0.012, S.E. = 0.005, P = 0.031) measures, whereas higher CSF t-tau levels were associated with poorer performance on measures of global cognition (ß = 0.022, S.E = 0.008, P = 0.007) and language (ß = -0.010, S.E = 0.004, P = 0.019). SSD was independently associated with diminished global cognition, learning and memory, language, and executive function performance over and above the effects of CSF biomarkers (all P < 0.05). CONCLUSIONS: MCI participants with SSD displayed diminished CSF Aß1-42 levels but did not differ from non-SSD controls in CSF tau levels. Additionally, CSF biomarkers and SSD independently accounted for variance in cognitive performance, suggesting that these factors may uniquely confer cognitive risk in MCI.

Depressive symptoms, post-traumatic stress symptoms and suicide risk among graduate students: The mediating influence of emotional regulatory self-efficacy.

The current study was to examine the relationship among depressive symptoms, post-traumatic stress symptoms, emotion regulatory self-efficacy and suicide risk. A cross-sectional survey was conducted among 3257 graduate students from a medical college of China. Lifetime prevalence of suicidal ideation, plan and attempt were 25.7%, 1.6%, 1.1%, respectively, with one-year suicidal ideation showing at 6.3%. Structural equation modeling was employed to examine the relative contribution of depressive symptoms, post-traumatic stress symptoms and emotion regulatory self-efficacy on suicide risk. Structural equation model had a highly satisfactory fit [χ2 = 7.782, df = 4, p = 0.096; RMSEA = 0.021; CFI = 0.992; GFI = 0.997]. Post-traumatic stress symptoms had a direct effect and an indirect effect on suicide risk via emotion regulatory self-efficacy. Depressive symptoms also had a direct effect and an indirect effect on suicide risk via emotion regulatory self-efficacy. The depressive and post-traumatic stress symptoms increased the risk of suicide risk, but the variable of emotion regulatory self-efficacy would be served as a buffering factor, decreasing the risk of suicide. The interaction term of depressive symptoms and post-traumatic stress symptoms had a direct effect on suicide risk. A significant interactive effect of depressive and post-traumatic stress symptoms on suicide risk was found.

Depression and fatigue in multiple sclerosis: Relation to exposure to violence and cerebrospinal fluid immunomarkers.

Multiple sclerosis (MS) is a neuroinflammatory condition characterized by chronic dysregulation of immune responses leading to repeated episodes of inflammation in the central nervous system. Depression and fatigue are common among MS patients, even in early disease phases, and the disease course can be negatively affected by stressful events. IL-6 and IL-8 have been associated with depression and stressful life events in non-MS patients. The aim of this study was to examine the relationships between depression, fatigue, and exposure to violence, with IL-6 and IL-8 levels in the cerebrospinal fluid (CSF) of MS patients. Levels of IL-6 and -8 were analyzed in the CSF of 47 patients with relapsing-remitting MS. Correlations between IL-6 and IL-8 levels and self-rated depression and fatigue symptoms, as well as clinician-rated history of being exposed to interpersonal violence, were analyzed with correction for age, sex and MS disability status. IL-6 correlated significantly (p < 0.05) with depressive symptoms (adjusted Spearman's ρ = 0.39), fatigue (ρ = 0.39), and exposure to violence in adult life (ρ = 0.35). Depression correlated with both fatigue and being exposed to violence. Associations were not present among patients exposed to disease modifying drugs. In exploratory analyses, the relationship between exposure to violence and IL-6 was non-significant when controlled for depression. Further research should focus on replication of these results, as well as exploring the impact of stressful life events on immune regulation and the clinical characteristics and prognosis of MS patients.

Evidence of cerebrospinal fluid abnormalities in patients with depressive syndromes.

BACKGROUND: Depression is the most prevalent psychiatric disease. In addition to primary, idiopathic depression, there are multiple secondary organic forms. However, distinguishing the two can be difficult, information about cerebrospinal fluid (CSF) basic findings in patients with depressive syndromes is sparse. Therefore, we investigated CSF alterations in so far the largest sample of patients with depressive syndromes. We hypothesized that increased prevalence of CSF pleocytosis, blood-brain-barrier (BBB) dysfunction, and oligoclonal bands (OCBs) would be observed as possible markers of underlying immunological processes. METHODS: From January 2006 until October 2013, we performed CSF basic diagnostics in 125 patients with depressive syndromes. We also performed serum and CSF autoantibody measurements, cerebral magnetic resonance imaging (cMRI) and electroencephalography (EEG). RESULTS: Four % of the patients displayed increased CSF white blood cell counts (WBC), 46.4% had increased protein concentrations, and 19.4% had pathological albumin quotients. OCBs in the CSF were detected in 6.5%. Overall, CSF basic diagnostics were abnormal in 56%. Including instrument-based diagnostics, we found alterations in 80.8% of patients. Suicidal tendencies correlated with an increased WBC count (r=0.276, p=0.002). LIMITATIONS: In this open, uncontrolled study, we investigated mainly CSF samples of depressive patients with signs of organic features. Therefore, the study cohort is not representative of idiopathic depression. CONCLUSIONS: The main findings of this study are the high rates of pathological (although mainly unspecific) CSF findings. We discuss the findings regarding possible immunological mechanisms and the vascular depression hypothesis. If these findings are associated with low-level inflammation of the central nervous system, new treatment alternatives could be considered. More and better controlled research is necessary.

A sensitive and practical RP-HPLC-FLD for determination of the low neuroactive amino acid levels in body fluids and its application in depression.

Ion-exchange high performance liquid chromatography (HPLC) generally fails as a method to determine low levels of free amino acids (AAs) in body fluids. Here we present a modified reversed-phase HPLC (RP-HPLC) protocol for the determination of AAs in body fluids and its application in mood disorder patients. We improved a previous research protocol by modifying i) sample preparation, including deproteination, ii) derivitization, including derivating agent and condition, and iii) sample separation, which is mainly determined by the pH value, the components and the additives of the mobile phases. The combination of these modifications, together with fluorescence detection (FLD), allows sensitive and practical determination of free AA levels in body fluids of depressive patients. This protocol was validated by determining the postmortem cerebrospinal fluid (CSF) glutamic acid (Glu) and γ-aminobutyric acid (GABA) levels of 8 major depressive disorder (MDD) patients, 9 bipolar disorder (BD) patients, and 19 well-matched controls, while also testing the plasma and CSF AA levels of living MDD patients. CSF Glu and GABA levels were both significantly decreased in MDD but not in BD patients. The data indicate that this RP-HPLC-FLD protocol is applicable for detection of low levels of neuroactive AAs in body fluids, as well as for routine clinical applications.

Plasma and cerebrospinal fluid amyloid-ß levels in late-life depression: A systematic review and meta-analysis.

This study aimed to evaluate differences in plasma and cerebrospinal fluid (CSF) levels of Aß peptides in older adults with late-life depression compared to non-depressed older controls. We conducted a systematic review and meta-analysis of the literature using PubMed, Web of science and Scopus databases with no search limits for publication dates or languages. Two independent reviewers extracted data and assessed quality. Six hundred references were retrieved, and we included 12 studies in the meta-analysis after eligibility screening. Older adults with late-life depression (LLD) had a higher plasma Aß40:Aß42 ratio compared to non-depressed participants (SMD = 1.10, CI95% [0.28; 1.96], p = 0.01), and marginally significant reduction of CSF Aß42 levels (SMD = -1.12, CI95% [-2.47; 0.22], p = 0.1). The present results evidence that older adults with depression have significant differences in Aß metabolism, in the same direction observed in individuals with AD. These differences in the Aß metabolism may help identify a subgroup of subjects with LLD at higher risk of developing AD.

Higher CSF interleukin-6 and CSF interleukin-8 in current depression in older women. Results from a population-based sample.

OBJECTIVE: The literature regarding cerebrospinal fluid (CSF) cytokines in geriatric depression is sparse. The aim of this study was to examine associations between CSF interleukin-6 (IL-6), interleukin-8 (IL-8) and depression in a population-based sample of older women who were followed for 17 years. METHODS: 86 dementia-free women aged 70-84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumbar puncture in 1992-3. CSF IL-6 and CSF IL-8 were measured. Psychiatric symptoms were rated with the Comprehensive Psychopathological Rating Scale at baseline and at three subsequent face-to-face examinations. Depression (major or minor) was diagnosed in accordance with DSM-IV/DSM-IV research criteria. RESULTS: At baseline, women with ongoing major (n=10) or minor depression (n=9) had higher levels of CSF IL-6 (p=0.008) and CSF IL-8 (p=0.007) compared with those without depression (n=67). Higher CSF IL-8 was related to higher MADRS score (p=0.003). New cases of depression were observed in 9 women during follow-ups. No associations between CSF cytokine levels and future depression could be shown in women without depression at baseline. CONCLUSION: Higher levels of CSF IL-6 and IL-8 were associated with current depression in this population-based sample. CSF IL-6 and CSF IL-8 may play a role in depression in late life.

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.

Cerebrospinal fluid space alterations in melancholic depression.

Melancholic depression is a biologically homogeneous clinical entity in which structural brain alterations have been described. Interestingly, reports of structural alterations in melancholia include volume increases in Cerebro-Spinal Fluid (CSF) spaces. However, there are no previous reports of CSF volume alterations using automated whole-brain voxel-wise approaches, as tissue classification algorithms have been traditionally regarded as less reliable for CSF segmentation. Here we aimed to assess CSF volumetric alterations in melancholic depression and their clinical correlates by means of a novel segmentation algorithm ('new segment', as implemented in the software Statistical Parametric Mapping-SPM8), incorporating specific features that may improve CSF segmentation. A three-dimensional Magnetic Resonance Image (MRI) was obtained from seventy patients with melancholic depression and forty healthy control subjects. Although imaging data were pre-processed with the 'new segment' algorithm, in order to obtain a comparison with previous segmentation approaches, tissue segmentation was also performed with the 'unified segmentation' approach. Melancholic patients showed a CSF volume increase in the region of the left Sylvian fissure, and a CSF volume decrease in the subarachnoid spaces surrounding medial and lateral parietal cortices. Furthermore, CSF increases in the left Sylvian fissure were negatively correlated with the reduction percentage of depressive symptoms at discharge. None of these results were replicated with the 'unified segmentation' approach. By contrast, between-group differences in the left Sylvian fissure were replicated with a non-automated quantification of the CSF content of this region. Left Sylvian fissure alterations reported here are in agreement with previous findings from non-automated CSF assessments, and also with other reports of gray and white matter insular alterations in depressive samples using automated approaches. The reliable characterization of CSF alterations may help in the comprehensive characterization of brain structural abnormalities in psychiatric samples and in the development of etiopathogenic hypotheses relating to the disorders.

Cerebrospinal fluid amyloid-ß 2-42 is decreased in Alzheimer's, but not in frontotemporal dementia.

Alzheimer's dementia (AD) and frontotemporal dementias (FTD) are common and their clinical differential diagnosis may be complicated by overlapping symptoms, which is why biomarkers may have an important role to play. Cerebrospinal fluids (CSF) Aß2-42 and 1-42 have been shown to be similarly decreased in AD, but 1-42 did not display sufficient specificity for exclusion of other dementias from AD. The objective of the present study was to clarify the diagnostic value of Aß2-42 peptides for the differential diagnosis of AD from FTD. For this purpose, 20 non-demented disease controls (NDC), 22 patients with AD and 17 with FTD were comparatively analysed by a novel sequential aminoterminally and carboxyterminally specific immunoprecipitation protocol with subsequent Aß-SDS-PAGE/immunoblot, allowing the quantification of peptides 1-38(ox), 2-40 and 2-42 along with Aß 1-37, 1-38, 1-39, 1-40, 1-40(ox) and 1-42. CSF Aß1-42 was decreased in AD as compared to NDC, but not to FTD. In a subgroup of the patients analyzed, the decrease of Abeta2-42 in AD was evident as compared to both NDC and FTD. Aß1-38 was decreased in FTD as compared to NDC and AD. For differentiating AD from FTD, Aß1-42 demonstrated sufficient diagnostic accuracies only when combined with Aß1-38. Aß2-42 yielded diagnostic accuracies of over 85 % as a single marker. These accuracy figures could be improved by combining Aß2-42 to Aß1-38. Aß2-42 seems to be a promising biomarker for differentiating AD from other degenerative dementias, such as FTD.

Doxepin concentrations in plasma and cerebrospinal fluid.

Doxepin--like other antidepressant drugs (ADs)--shows a variable antidepressant effect in clinical practice. The cause for this variability is as yet unclear; however, pharmacokinetic factors such as the variable permeability of doxepin into the cerebrospinal fluid (CSF), may contribute to the difference in therapeutic efficacy. We measured and correlated the concentration of doxepin and its active metabolite nordoxepin in both the plasma and CSF. Plasma and CSF samples were taken simultaneously from 21 patients who were treated with doxepin due to different clinical indications. The plasma concentration of both doxepin and nordoxepin correlated significantly with the oral dosage of doxepin (doxepin: r = +0.66, p < 0.001; nordoxepin: r = +0.78, p < 0.0001; Spearman's correlation). Furthermore, we found significant correlations between the plasma and CSF concentrations of both doxepin (r = +0.71; p < 0.001; Pearson's correlation) and nordoxepin (r = +0.74; p < 0.001). These highly significant correlations between the plasma and CSF concentrations indicate a constant CSF permeability of doxepin and its active metabolite nordoxepin.

Familial paroxysmal exercise-induced dystonia: atypical presentation of autosomal dominant GTP-cyclohydrolase 1 deficiency.

Paroxysmal exercise-induced dystonia (PED) is one of the rarer forms of paroxysmal dyskinesia, and can occur in sporadic or familial forms. We report a family (male index case, mother and maternal grandfather) with autosomal dominant inheritance of paroxysmal exercise-induced dystonia. The dystonia began in childhood and was only ever induced after many minutes of exercise, and was never present at rest, or on initiation of movements. In addition, family members suffered restless legs syndrome (RLS), depression, and adult-onset Parkinsonism. The index case had low cerebrospinal fluid neurotransmitters and pterins. The PED and RLS stopped on initiation of L-Dopa therapy. Both live family members were found to have a nonsense mutation (p.E84X) in exon 1 of the GTP-cyclohydrolase 1 (GCH-1) gene. We propose that GCH-1 mutations should be considered a genetic cause of familial PED, especially if additional clinical features of monoaminergic deficiency are present in affected individuals.

Cerebrospinal fluid monoamine metabolites and suicide.

Prospective studies of the serotonergic system and suicide report that low 5-hydroxyindolacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) and a history of attempted suicide predict suicide risk. Low CSF homovanillic acid (HVA) is reported to be associated with past and future lethality of suicide attempts but not with suicide. The interrelationships between monoamine metabolites, violent method, suicide intent and lethality of suicidal behaviour are complex. We hypothesized that CSF 5-HIAA and HVA levels are related to suicide intent, violence and lethality of suicidal behaviour. Fifteen male suicide attempters admitted to a psychiatric ward at the Karolinska University Hospital and eight healthy male volunteers were submitted to lumbar puncture and CSF 5-HIAA and HVA were assayed. Suicide intent with the Beck Suicide Intent Scale (SIS), lethality and violence of suicidal behaviour were assessed. All patients were followed up for causes of death. Six suicides and one fatal accident were identified with death certificates. Mean CSF 5-HIAA but not CSF HVA differed between suicides and survivors. Violent suicides had higher suicide intent and CSF 5-HIAA than non-violent suicides. In violent suicides, CSF 5-HIAA levels were negatively correlated with SIS. Greater suicide intent may be associated with greater aggressive intent and predicts a violent suicide method.

Activation of central nervous system inflammatory pathways by interferon-alpha: relationship to monoamines and depression.

BACKGROUND: Interferon (IFN)-alpha has been used to study the effects of innate immune cytokines on the brain and behavior in humans. The degree to which peripheral administration of IFN-alpha accesses the brain and is associated with a central nervous system (CNS) inflammatory response is unknown. Moreover, the relationship among IFN-alpha-associated CNS inflammatory responses, neurotransmitter metabolism, and behavior has yet to be established. METHODS: Twenty-four patients with hepatitis C underwent lumbar puncture and blood sampling after approximately 12 weeks of either no treatment (n = 12) or treatment with pegylated IFN-alpha 2b (n = 12). Cerebrospinal fluid (CSF) and blood samples were analyzed for proinflammatory cytokines and their receptors as well as the chemokine, monocyte chemoattractant protein-1 (MCP-1), and IFN-alpha. Cerebrospinal fluid samples were additionally analyzed for monoamine metabolites and corticotropin releasing hormone. Depressive symptoms were assessed using the Montgomery Asberg Depression Rating Scale. RESULTS: Interferon-alpha was detected in the CSF of all IFN-alpha-treated patients and only one control subject. Despite no increases in plasma IL-6, IFN-alpha-treated patients exhibited significant elevations in CSF IL-6 and MCP-1, both of which were highly correlated with CSF IFN-alpha concentrations. Of the immunologic and neurotransmitter variables, log-transformed CSF concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), were the strongest predictor of depressive symptoms. Log-transformed CSF concentrations of IL-6, but not IFN-alpha or MCP-1, were negatively correlated with log-transformed CSF 5-HIAA (r(2) = -.25, p < .05). CONCLUSIONS: These data indicate that a peripherally administered cytokine can activate a CNS inflammatory response in humans that interacts with monoamine (serotonin) metabolism, which is associated with depression.