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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 × 10 6 /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., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The importance of cerebrospinal fluid (CSF) diagnostics for psychiatry is growing. The CSF/blood albumin quotient (Q Alb ) is considered to be a measure of the blood-CSF barrier function. Recently, systematically higher Q Alb 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 Q Alb 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 Q Alb mean values and chi 2 -testing for the number of increased age-corrected Q Alb levels to investigate sex differences in Q Alb ., Results: The Q Alb 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 (chi 2  = 42.625, p < 0.001). The mean Q Alb 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 Q Alb 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.

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., Competing Interests: The authors have declared that no competing interests exist.

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., (Copyright © 2018. Published by Elsevier B.V.)

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., (Copyright © 2018. Published by Elsevier B.V.)

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 (Aβ 1-42 ), 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 Aβ 1-42 levels (β = -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 Aβ 1-42 levels were associated with poorer performance on learning (β = 0.041, S.E. = 0.018, P = 0.021) and memory (β = -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 (β = 0.022, S.E = 0.008, P = 0.007) and language (β = -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 Aβ 1-42 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., (Copyright © 2018 John Wiley & Sons, Ltd.)

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 [χ 2  = 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

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-β42 [Aβ42], 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.

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., (Copyright © 2016 Elsevier B.V. All rights reserved.)

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., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

This study aimed to evaluate differences in plasma and cerebrospinal fluid (CSF) levels of Aβ 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 Aβ40:Aβ42 ratio compared to non-depressed participants (SMD = 1.10, CI95% [0.28; 1.96], p = 0.01), and marginally significant reduction of CSF Aβ42 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 Aβ metabolism, in the same direction observed in individuals with AD. These differences in the Aβ metabolism may help identify a subgroup of subjects with LLD at higher risk of developing AD., Competing Interests: The authors do not have any conflict of interest to report regarding this manuscript., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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.

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) Aβ2-42 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 Aβ2-42 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 Aβ-SDS-PAGE/immunoblot, allowing the quantification of peptides 1-38(ox), 2-40 and 2-42 along with Aβ 1-37, 1-38, 1-39, 1-40, 1-40(ox) and 1-42. CSF Aβ1-42 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. Aβ1-38 was decreased in FTD as compared to NDC and AD. For differentiating AD from FTD, Aβ1-42 demonstrated sufficient diagnostic accuracies only when combined with Aβ1-38. Aβ2-42 yielded diagnostic accuracies of over 85 % as a single marker. These accuracy figures could be improved by combining Aβ2-42 to Aβ1-38. Aβ2-42 seems to be a promising biomarker for differentiating AD from other degenerative dementias, such as FTD.

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.

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.

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.

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.

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.

A lower thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) in depressed women has been associated with violent suicide attempts, suicidal intent, higher lethality and suicide risk. The cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) levels are related to suicidal behaviour. We studied the HPT axis function in twelve male suicide attempters and eight healthy volunteers submitted to lumbar puncture and to TRH test. Suicidal behaviour and depression severity were assessed. There was no association between deltamaxTSH and violent suicidality or subsequent suicide. The deltamaxTSH correlated with CSF HVA in suicide attempters. The plasma T3 showed a negative correlation with the Beck Suicide Intent Scale and the Montgomery Asberg Depression rating scale. Dopaminergic regulatory mechanisms on the thyroid hormone activity may be altered in male suicide attempters.

Background: Two major biomarkers of suicidal behaviour; low 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) and non-suppression in the dexamethasone suppression test (DST) have evidence for predictive power for suicide in mood disorders. Previous suicide attempt is the most robust clinical risk factor., Purpose of Study: To study the interrelationship of suicide risk factors: low CSF 5-HIAA and the DST non-suppression in mood disorder patients with and without an index suicide attempt., Methods: Fifty-eight hospitalised mood disorder patients (twenty-five with an index suicide attempt), who were not receiving any treatment with antidepressants, underwent lumbar puncture and DST. Plasma cortisol levels were determined from blood samples drawn the following day at 8:00 a.m., 4:00 p.m. and 11:00 p.m. and analysed in relation to CSF 5-HIAA., Results: In the sample as a whole, the serum cortisol level at 4:00 p.m. showed a significant positive correlation to CSF 5-HIAA (r=0.3, p<0.02). In the patients with an index suicide attempt, the serum cortisol at 4.00 p.m. correlated positively with CSF 5-HIAA (r=0.65, p<0.0006), but not in the non-attempters (NS)., Conclusion: The positive correlation means that low CSF 5-HIAA and DST non-suppression are relatively independent biomarkers of suicide risk in suicide attempters. The interrelation of the two systems seems to be different in suicide attempters compared to depressed inpatients without suicide attempt.

The serotonin (5-hydroxytryptamine) transporter (5-HTT) is considered to affect the pathogenesis of mood disorders. Large number of genetic association studies between 5-HTT functional polymorphisms and vulnerability of mood disorders and therapeutic response to antidepressants has been carried out. We investigated the influence of 5-HTT-linked polymorphic region (5-HTTLPR) and 5-HTT 17 bp variable number of tandem repeat polymorphism (5-HTTVNTR) polymorphisms on concentrations of monoamine metabolites in cerebrospinal fluid (CSF) among treatment-resistant patients with mood disorders. Subjects were 119 Swedish patients with persistent mood disorders and 141 healthy subjects. In 112 of these patients, we measured 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol in CSF. Genotyping for 5-HTT polymorphisms from genomic DNA was carried out by PCR. There was no significant difference in allele/genotype frequency between patients and healthy subjects. In patients with mood disorders, we found significant difference in mean 5-HIAA concentration between 5-HTTLPR genotypes (p=0.03). Although the 5-HIAA concentration showed a tendency to be higher in short (S) carriers than in non-S carriers of the 5-HTTLPR in patients (p=0.06), when considering patients with major depressive disorder (MDD), the 5-HIAA concentration was significantly higher among S carriers than among non-S carriers (p=0.02). Moreover, the 5-HIAA concentration was higher in S/S subjects compared to long (L)/L (p=0.0001) and L/S (p=0.002) subjects in patients with MDD. Similarly, there was higher HVA concentration in S/S subjects compared to L/L (p=0.002) and L/S subjects (p=0.002). There was no effect of 5-HTTVNTR. Our findings show that the 5-HTTLPR polymorphism affects 5-HIAA and HVA concentrations among treatment-resistant patients with mood disorders.

Dysregulation of the monoaminergic systems is likely a sufficient but not a necessary cause of depression. A wealth of data indicates that neuropeptides, e.g., NPY, CRH, somatostatin, tachykinins and CGRP play a role in affective disorders and alcohol use/abuse. This paper focuses on NPY in etiology and pathophysiology of depression. Decreased peptide and mRNA NPY were found in hippocampus of both the genetic, e.g., the FSL strain, and environmental rat models of depression, e.g., chronic mild stress and early life maternal separation paradigms. Rat models of alcoholism also show altered NPY. Furthermore, NPY is also reduced in CSF of depressed patients. Antidepressive treatments tested so far (lithium, topiramate, SSRIs, ECT and ECS, wheel running) increase NPY selectively in rat hippocampus and in human CSF. Moreover, NPY given icv to rat has antidepressive effects which are antagonized by NPY-Y1 blockers. The data support our hypothesis that the NPY system dysregulation constitutes one of the biological underpinnings of depression and that one common mechanism of action of antidepressive treatment modalities may be effects on NPY and its receptors. In a novel paradigm, early life maternal separation was superimposed on "depressed" FSL and control rats and behavioral and brain neurochemistry changes observed in adulthood. The consequences were more deleterious in genetically vulnerable FSL. Early antidepressive treatment modulated the adult sequelae. Consequently, if these data are confirmed, the ethical and medical question that will be asked is whether it is permissible and advisable to consider prophylactically treating persons at risk.

Background: The orexins (hypocretins) are recently discovered hypothalamic peptides that are involved in the regulation of sleep, appetite and state of arousal. In the present study, we investigated the relationship between cerebrospinal fluid (CSF) orexin and specific psychiatric symptoms in suicidal patients., Methods: A total of 101 patients were enrolled in the study shortly after a suicide attempt. All patients underwent a lumbar puncture after a wash-out period during which they did not receive any antipsychotic or antidepressive medication. Structured interviews were performed using the Comprehensive Psychopathological Rating Scale (CPRS). CSF-orexin-A was measured and correlated with ratings of psychiatric symptoms., Results: There were significant and negative correlations between CSF-orexin and the symptoms lassitude (difficulty to initiate activities) and slowness of movement, as well as the ratings of global illness (p<0.005 for all three items, Spearman's rho)., Limitations: Correlation analysis is an indirect method of investigation and does not demonstrate causal relationships., Conclusion: Low CSF-orexin levels are related to pronounced symptoms of inertia and reduced motor activity in suicidal patients. Interestingly, the lower the orexin levels, the higher were ratings of overall illness, as observed by a specialist in psychiatry. Our results suggest that reduced orexin levels are involved in the etiology of specific psychiatric symptoms.

Significantly increased cerebrospinal fluid (CSF) total tau (t-tau) and phosphorylated at threonine 181 tau (p-tau) levels were frequently found in patients with mild cognitive impairment (MCI) who have an increased risk of developing Alzheimer's disease (AD). Though MCI often overlaps with depressive symptoms making early diagnosis difficult, to date no CSF marker has been probed to support the differential diagnosis of geriatric major depressive disorder and MCI eventually converting to AD. CSF levels of t-tau and p-tau were determined by ELISA in 80 subjects with MCI (aging associated cognitive decline criteria), 54 patients with major depression and 24 cognitively healthy controls. Patients were reassessed after a follow-up period of at least 12 month. During follow-up, 29% of the MCI patients but only one patient with major depression converted to AD. Already at baseline converters to AD were characterized by significantly higher t-tau and p-tau levels compared to non-converters and the other diagnostic groups. Our findings demonstrate that both, CSF t-tau and p-tau levels facilitate the differential diagnosis of MCI and are of prognostic value.

There is a need to find stable biomarkers for suicidal behavior and suicide prediction. Reduced homovanillic acid/5-hydroxyindolacetic acid (HVA/5-HIAA) ratios in cerebrospinal fluid (CSF) in depressed suicide attempters have been reported. Suicide intent is a predictor of repetition of attempts and suicide. In the present study we investigated the relationship of HVA/5-HIAA ratio to the scales rating suicide intent and depressive symptoms. Fifteen consecutive medication-free male suicide attempters admitted to a psychiatric ward at the Karolinska Hospital and eight healthy male volunteers underwent lumbar puncture and had the CSF monoamine metabolite levels assayed. Patients were assessed with the Beck Suicide Intent Scale (SIS), the Montgomery Asberg Depression rating Scale (MADRS) and the Chapman Scale of Anhedonia. Within the suicide attempter group, HVA/5-HIAA ratio was significantly associated with the Suicide Intent Scale (SIS), but not with the MADRS scale or the Chapman Scale of Anhedonia indicating that the HVA/5-HIAA ratio may be a biomarker of suicide intent.

Psychiatric comorbidity is one of the key elements in chronic migraine (CM) management. Depression is particularly common in these patients, occurring in up to 85%. Preclinical studies have suggested that gamma-aminobutyric acid (GABA) levels may be decreased in animal models of depression. Also, clinical studies have reported low level in mood disorder patients for both plasma and cerebrospinal fluid (CSF) GABA. We hypothesized that low GABA levels in the brain might be related to the depression associated with CM. We studied 14 chronic migraine patients, with or without depression, compared to age-and sex-matched controls. CSF GABA levels were measured by HPLC. CSF GABA levels showed significant lower levels in depressed patients than those without depression. No difference was found when comparing patients versus controls. A GABA deficiency may be the underlying mechanism of depression in CM. Hence, preventive therapies modulating GABA neurotransmission could be used in CM associated with depression.

Hypothalamo-pituitary-adrenal (HPA)-axis hyperactivity is well established in a large proportion of both Alzheimer's disease (AD) patients and idiopathic depression patients, resulting in, e.g. increased cerebrospinal fluid (CSF) cortisol levels. We hypothesized that HPA-axis activity in depressed AD patients is even more increased than in non-depressed AD patients, resulting in higher CSF cortisol levels. Cortisol levels were measured in post mortem CSF of depressed and non-depressed AD patients and in controls. Cortisol levels in AD patients were more than double those of controls, while no significant differences were found between depressed and non-depressed AD patients. These results suggest a different pathogenetic mechanism in depression in AD than in idiopathic depression.

Little information exists on the concentrations of recent antidepressants and their metabolites in cerebrospinal fluid (CSF). Using a stereoselective method, we measured plasma and CSF levels of mirtazapine (MIR), N-demethylmirtazapine and 8-OH-MIR in 3 depressed patients treated with racemic MIR (45 mg/day) for 4 weeks. S-(+)-MIR is considered to be the antidepressant enantiomer, but only R-(-)-MIR reached measurable concentrations in CSF. For R-(-)-MIR, the CSF/plasma ratio varied between 0.08 and 0.31. Further studies are needed to test the hypothesis that there are possible differences in the transport mechanisms of the enantiomers of MIR at the blood-CSF barrier., (2006 S. Karger AG, Basel)

Unlabelled: Depression is characterized by blunted behavior and neuroendocrine function that generally improve with antidepressant treatment. This study examined intrinsic variability in brain neurotransmitter function, since it may be a source of blunted behavior and neuroendocrine function in depression and a marker for the illness, and has not previously been analyzed using wavelet decomposition. To measure variability in monoamine metabolites, lumbar cerebrospinal fluid (CSF) was collected in serial samples in depressed patients before and after treatment. We hypothesized that changes in variability would be observed after treatment. Mechanisms that control such variability may be critical to the pathophysiology of depression., Method: Time series data was obtained from serial ten-min sampling over a 24-hr period (N=144) from thirteen depressed patients, with a repeat collection after 5 weeks of antidepressant (sertraline or bupropion) treatment. Concentrations of tryptophan (TRP), the monoamine metabolites 5-HIAA (metabolite of serotonin) and HVA (metabolite of dopamine), and the HVA:5HIAA ratio were transformed to examine power in slowly (160 min/cycle) to rapidly (20 min/cycle) occurring events. Power, the sum of the squares of the coefficients in each d (detail) wavelet, reflects variability within a limited frequency bandwidth for that wavelet. Pre-treatment to post-treatment comparisons were conducted with repeated measures ANOVA., Results: Antidepressant treatment was associated with increased power in the d2 wavelet from the HVA (p=0.03) and the HVA:5-HIAA ratio (p=0.03) series. The d1 and d3 wavelets showed increased power following antidepressant treatment for the ratio series (d1, p=0.01; d3, p=0.05). Significant changes in power were not observed for the 5-HIAA data series. Power differences among analytes suggest that the findings are specific to each system., Conclusion: The wavelet transform analysis shows changes in neurochemical signal variability following antidepressant treatment. Patterns or degrees of variability may be as important as, or possibly more important than, the mean levels of monoamine transmitters. Studies of variability observed in healthy individuals and a larger depressed sample will be needed to verify a relationship with mood and treatment response. Neurochemical measures of time-variability may be a pivotal marker in depression.

Background: Leptin is a hormone known to participate in the regulation of weight and appetite and is therefore of interest to examine in the context of major depressive disorder (MDD). Studies of circulating leptin have yielded variable results. We therefore decided to study leptin in cerebrospinal fluid (CSF)., Methods: We measured leptin in cerebrospinal fluid (CSF) in 72 patients admitted after a suicide attempt. They were divided in two groups: patients with major depressive disorder (MDD) and patients with other diagnoses (non-MDD). They were also subgrouped according to the number of suicide attempts (one or repeated) and whether the suicide attempt method was classified as violent or nonviolent. Since CSF leptin was considerably lower in men than in women, statistical calculations were made for men and women separately., Results: We found that in spite of having similar body mass index (BMI) (P = 0.1), women in the MDD group had lower CSF leptin than those in the non-MDD group (P < 0.01). In contrast, no such difference was found among men. No significant differences were found between women with a first suicide attempt compared to those with a repeated one, or between women with a violent attempt compared to those with a nonviolent attempt., Limitations: The heterogeneity of the non-MDD group including patients with various diagnoses is the most important limitation of our study., Conclusions: CSF leptin is involved in the neuroendocrine dysfunction in women with suicide attempt and MDD. This finding contributes to the understanding of the metabolic symptoms in MDD.

Major depression and alcoholism are often comorbid, resulting in more impairment and more suicidal behavior compared with either diagnosis alone. This study compared clinical features and cerebrospinal fluid (CSF) monoamine metabolites in depressed subjects with and without a history of alcoholism and healthy volunteers. We hypothesized that depressed subjects with a history of alcoholism would be more aggressive, impulsive, and suicidal than depressed subjects without a history of alcoholism, and would have lower CSF monoamine metabolite levels. We compared 63 subjects with a current major depressive episode (MDE) and a history of alcoholism, 72 subjects with a current MDE but without a history of alcoholism, and 22 healthy volunteers. Participants with a history of alcoholism were in remission for at least 6 months. All subjects were free from prescribed medications known to affect brain serotonin, dopamine, or norepinephrine systems for a minimum of 14 days. Depressive symptoms, lifetime aggression, impulsivity, Axis II disorders, and suicidal behavior were assessed. CSF was sampled and homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) were assayed by high-performance lipid chromatography with electrochemical detection. Depressed subjects with a history of alcoholism did not differ from depressed subjects without a history of alcoholism in current severity of depressive symptoms, or in past suicidal behavior. Depressed subjects with a history of alcoholism had lower CSF HVA levels, and higher lifetime aggression and current suicide ideation scale scores and were more likely to be tobacco smokers compared with depressed subjects without a history of alcoholism. Low HVA was present after adjustment for sex, aggression and depression scores, cigarette smoking, antisocial and borderline personality disorders, psychomotor retardation, and delusions. Controls had CSF HVA levels intermediate between the two depressed groups. We found no group difference in CSF 5-HIAA and MHPG levels. In individuals with current MDE, those with a history of comorbid alcoholism had lower CSF HVA levels compared with those without a history of alcoholism. Low CSF HVA suggests that impaired dopaminergic activity is associated with a history of alcoholism in persons with current MDE.

Objective: Outward-directed violence and impulsivity in humans and primates has frequently been related to abnormal brain monoaminergic turnover. Self-rated aggression is likely to be clinically relevant,and its psychobiological basis needs investigation., Subjects: Sixty-six patients (40 women and 26 men) with persistent depressive disorder (PDD) were compared with 497 control subjects from the general Swedish population., Methods: We administered the Aggression Questionnaire - Revised Swedish Version (AQ-RSV) to patients and control subjects. In patients, CSF 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-5-hydroxyphenylglycol (MHPG) in CSF were analyzed. Total Aggression score and Aggression subfactors 'Physical Aggression','Verbal Aggression','Anger', and 'Hostility'were correlated with CSF concentrations of 5-hydroxyindoleacetic acid (5-HIAA),and 3-methoxy-5-hydroxyphenylglycol (MHPG)., Results: Overall, Hostility was positively related to CSF MHPG (t=2.27, p=0.015). Split by sex,Hostility was related with 5-HIAA in males (r=0.62,p=0.003),and with MHPG in females (r=0.38, p=0.03). Comparing self rated aggression with age- and sex-matched data from the general Swedish population, the most prominent deviation was increased Hostility score among PDD patients. Among patients, all aggression factors were nominally higher in women than in men, with the most pronounced sex difference in Hostility (t=-1.89, p=0.04)., Conclusions: Results suggest a clinically meaningful sex difference in a positive relationship between hostility and serotonergic/noradrenergic turnover in PDD patients.

Background: Hypocretins, excitatory neuropeptides at monoaminergic synapses, appear to regulate human sleep-wake cycles. Undetectable cerebrospinal fluid hypocretin-1 levels are seen in narcolepsy, which is frequently associated with secondary depression. Shortened rapid eye movement latency is observed in both narcolepsy and depression. Cerebrospinal fluid hypocretin-1 levels have not been reported in mood disorders., Methods: We examined hypocretin-1 levels in 14 control and 15 depressed subjects. Cerebrospinal fluid was drawn continuously in supine subjects for 24 hours with an indwelling intrathecal catheter under entrained light-dark conditions. Depressed subjects were studied before and after 5 weeks of sertraline (n=10, three nonresponders) or bupropion (n=5, two nonresponders)., Results: Hypocretin-1 levels varied slightly (amplitude 10%) but significantly across the diurnal cycle in control subjects, with amplitude significantly reduced in depression (3%). Levels were lowest at midday, surprising for a hypothetically wake-promoting peptide. Mean hypocretin levels trended higher in depressive than in control subjects. Hypocretin-1 levels decreased modestly but significantly after sertraline (-14%) but not bupropion., Conclusions: Our results are consistent with previous physiologic findings in depression indicating dampened diurnal variations in hypocretin-1. The finding that sertraline but not bupropion slightly decreased cerebrospinal fluid hypocretin-1 indicates a serotoninergic influence on hypocretin tone.

This study tested suicidality in relation to cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and the dexamethasone suppression test. Patients with nonsuppression of cortisol had the highest scores of the Suicide Assessment Scale (SUAS) and the Montgomery Asberg Depression Rating Scale (MADRS), respectively (P < 0.05; P < 0.01). The results persisted when analysed for covariance with CSF-5-HIAA. We have previously noted an elevated suicide risk in suicide attempters with high SUAS-scores, why a large part of nonsuppressors may be at high risk for future suicide.

Background: We tested if duration and intensity of episodes in treatment-resistant affectively ill patients were related to cerebrospinal fluid (CSF) concentrations of monoamine metabolites., Method: In retrospective life charts were recorded every previous episode of 37 patients with severe treatment-refractory affective disorders. 'Accumulated burden of mood swings' (ABMS, sum of each episode length x episode depth) was used to estimate the accumulated illness burden. Homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were analyzed in CSF of all patients and compared with 27 healthy controls. Data were analyzed using multiple regression analysis., Results: CSF MHPG contributed strongly significant and positively to the ABMS., Limitations: The retrospective nature of the study., Conclusion: CSF concentrations of MHPG is positively related to ABMS over life. Thus, a specific involvement of norepinephrine in the long-term burden of affective illness is a likely reality.

Objective: Cigarette smoking is associated with a higher risk for suicide and attempted suicide, but psychopathological or biological explanations for this association have not been explored. Lower serotonin function and impulsive/aggressive traits are associated with suicidal acts, including completed suicide. The authors hypothesized that the relationship that may exist between cigarette smoking and suicidal behavior may be associated with lower serotonin function and the presence of impulsive/aggressive traits., Method: Study subjects were 347 patients with a psychiatric disorder (175 with depression, 127 with schizophrenia, and 45 with other disorders). Fifty-three percent of the subjects (N=184) had a lifetime history of suicide attempt, and 47% (N=163) had never attempted suicide. Smoking behavior, lifetime suicidal behavior, and psychopathology were assessed. Serotonin function was assessed in a subgroup of patients with depression (N=162) by using a fenfluramine challenge test and/or measurement of CSF levels of 5-hydroxyindoleacetic acid., Results: Among all patients, smokers were more likely to have made a suicide attempt (adjusted odds ratio=2.60, 95% confidence interval=1.60-4.23) and had higher suicidal ideation and lifetime aggression scores, compared with nonsmokers. An inverse relationship was observed between amount of cigarette smoking and both indices of serotonin function., Conclusions: The association between cigarette smoking and the presence and severity of suicidal behavior across major psychiatric disorders may be related to lower brain serotonin function in smokers with depression. Further investigation is required to replicate these findings, to measure serotonin function in patients with disorders other than depression, and to test potential therapeutic effects of serotonin-enhancing treatments on both smoking behavior and suicide risk.

Objective: Differentiation of geriatric major depression from Alzheimer's disease is hampered by overlapping symptoms. Increased CSF concentrations of tau protein phosphorylated at threonine 231 (p-tau(231)) have been suggested as a biomarker for Alzheimer's disease. The authors asked whether p-tau(231) levels improve the differential diagnosis between geriatric major depression and Alzheimer's disease., Method: Included were 34 depression subjects, 64 with probable Alzheimer's disease, 17 with possible Alzheimer's disease, and 21 healthy comparison subjects. P-tau(231) concentrations were measured with an enzyme-linked immunosorbent assay., Results: P-tau(231) levels were significantly higher in Alzheimer's disease than in geriatric major depression patients and healthy comparison subjects. For differentiation of probable Alzheimer's disease from major depression, p-tau(231) correctly allocated 87% of subjects. When possible mild Alzheimer's disease was compared to major depression, p-tau(231) correctly allocated 78% of subjects., Conclusions: CSF p-tau(231) should be evaluated as a potential biological marker for differentiation of geriatric depression from Alzheimer's disease.

Background: Structural brain abnormalities are prevalent in patients with schizophrenia and affective disorders., Aims: To study how regional brain volumes and their ratios differ between patients with schizophrenia, psychotic depression, severe non-psychotic depression and healthy controls., Method: Magnetic resonance imaging scans of the brain on first-episode patients and on healthy controls., Results: Patients with schizophrenia had a smaller left frontal grey matter volume than the other three groups. Patients with psychotic depression had larger ventricular and posterior sulcal cerebrospinal fluid (CSF) volumes than controls. Patients with depression had larger white matter volumes than the other patients., Conclusions: Left frontal lobe, especially its grey matter volume, seems to be specifically reduced in first-episode schizophrenia. Enlarged cerebral ventricles and sulcal CSF volumes are prevalent in psychotic depression. Preserved or expanded white matter is typical of non-psychotic depression.

Cerebrospinal fluid (CSF) was obtained from 32 patients with dementia, 19 healthy controls that were age-matched with the dementia patients, and 29 DSM-IV major depression patients and calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) and calcitonin-like immunoreactivity (CT-LI) measured by RIA. CGRP-LI was lower in the dementia group compared to both the controls and depressed patients (P<.01) after covarying out sex and age. CT-LI was decreased in the dementia and depressed patients (P<.05) compared to the controls. A positive relationship between CGRP-LI and CT-LI was found in dementia. A logistic discriminant analysis with calcitonin gene-related peptide (CGRP) and log calcitonin (CT) predicting diagnosis (three classes) revealed a significant overall fit (chi2 = 18.08, P = .0011), with an effect test showing contributions of both independent variables: CGRP (chi2 = 10.03, P<.007), log CT (chi2 = 8.63, P = .013). In dementia, both CGRP-LI and CT-LI were decreased and their concentration ratio did not differ from that in controls, likely reflecting a general neuronal loss. Alternatively and more speculatively, but theoretically possible, expression of the alpha-CGRP/CT gene may be affected in dementia. In contrast, in depression, CT-LI but not CGRP-LI was decreased and the CGRP/CT concentration ratio was increased, which is consistent with a possibility of an altered splicing process favoring CGRP mRNA.

This study describes the changes in cerebrospinal fluid (CSF) monoamine metabolites during antidepressant treatment for more than 6 months. Eight patients, who received antidepressant treatment after attempted suicide and then underwent lumbar punctures every 3 or 4 months, were included. Plasma drug concentrations and the clinical outcome were also measured. Consistent with previous reports about antidepressant treatment for between 3 and 6 weeks, both 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly decreased after treatment for a mean of 15 weeks compared to pretreatment. However, after continued treatment for a mean of 30 weeks the MHPG concentration remained significantly lower than at pretreatment while 5-HIAA had returned to the pretreatment level. The clinical outcome was significantly correlated to the pretreatment 5-HIAA/MHPG ratio. These results suggest that the frequently reported reduction in CSF 5-HIAA after antidepressant treatment does not remain during long-term treatment.

Background: There is increasing evidence for an association between alterations of brain glutamatergic neurotransmission and the pathophysiology of affective disorders., Methods: We studied the association between cerebrospinal fluid (CSF) metabolites, including glutamine, in unipolar and bipolar depressed patients versus control subjects using a proton magnetic resonance spectroscopy technique. Cerebrospinal fluid samples were obtained from 18 hospitalized patients with acute unmedicated severe depression without medical problems and compared with those of 22 control subjects., Results: Compared with the control group, the depressed patient group had significantly higher CSF glutamine concentrations, which correlated positively with CSF magnesium levels., Conclusions: These findings suggest an abnormality of the brain glial-neuronal glutamine/glutamate cycle associated with N-methyl-D-aspartate receptor systems in patients with depression.

Analysis of cerebrospinal fluid (CSF) metabolites can provide data regarding CNS involvement in neurologic and psychiatric illness. However, there is lack of research into the effect of processing and storage of CSF specimens on the levels of metabolites analyzed. CSF specimens from 10 depressed patients were analyzed by proton NMR before and after 72 hours exposure to room temperature. No effect of exposure was found on myoinositol, glucose, acetate, and alanine CSF levels and there was a substantial decrease of citrate (>50%) and increase in lactate, glutamine, creatine, and creatinine levels.

There is increasing evidence for an association between the alteration of cytokine concentrations in blood and the pathophysiology of depressive disorders. Studies in humans have not investigated CSF cytokine concentrations and their relationship to depressive disorders. This study reports on the association of the CSF concentration of proinflammatory cytokines, IL-1beta, IL-6 and TNFalpha, and major depressive disorders. CSF samples were obtained from 13 hospitalized patients with acute unmedicated severe depression and were compared with 10 control subjects. Compared to the control group, the depressed patient group had higher CSF concentrations of IL-1beta, lower IL-6 and no change in TNFalpha. A positive correlation was found between serum IL-1beta and the severity of depression. These results indicate a unique profile for CSF proinflammatory cytokines in acute depression. These findings merit further investigation and if replicated may possibly offer immunological treatment options for depression.

Objective: Transthyretin plays an important role in the transport and distribution of thyroid hormone in the central nervous system (CNS). This study replicated and extended to patients with nonrefractory depressive illness a pilot study indicating that patients with refractory major depression have significantly lower levels of CSF transthyretin than do healthy comparison subjects., Method: Lumbar punctures were performed in drug-free subjects with DSM-III-R major depression (N = 18), DSM-III-R bipolar disorder, depressed phase (N = 1), and healthy comparison subjects (N = 24). CSF concentrations of transthyretin, determined by a quantitative dot-immunobinding assay, of the depressed patients and comparison subjects were compared by analysis of covariance (ANCOVA). The relationship between CSF transthyretin levels and Hamilton Depression Rating Scale scores was determined in a subset of the depressed patients., Results: CSF concentrations of transthyretin were significantly lower in the depressed patients than in the comparison subjects by ANCOVA. Within the depressed group there was no significant overall correlation between CSF transthyretin levels and Hamilton depression scale scores, but there was a significant inverse correlation in male depressed patients (N = 8) between CSF transthyretin concentrations and Hamilton depression scores., Conclusions: Lower CSF transthyretin concentrations in depressed patients may reflect either a stable trait in this population or a state change secondary to depression or other factors. Lower CSF transthyretin concentrations may result in altered CNS thyroid hormone homeostasis. Such alteration could account for certain mood and neurovegetative symptoms of depression and might contribute to failure of standard antidepressant treatment.