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1.
J Psychiatr Res ; 135: 294-301, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33524676

RESUMO

Fear conditioning and generalization are well-known mechanisms in the pathogenesis of anxiety disorders. Extinction of conditioned fear responses is crucial for the psychotherapeutic treatment of these diseases. Anxious depression as a subtype of major depression shares characteristics with anxiety disorders. We therefore aimed to compare fear learning mechanisms in patients with anxious versus non-anxious depression. Fear learning mechanisms in patients with major depression (n = 79; for subgroup analyses n = 41 patients with anxious depression and n = 38 patients with non-anxious depression) were compared to 48 healthy participants. We used a well-established differential fear conditioning paradigm investigating acquisition, generalization, and extinction. Ratings of valence, arousal and probability of expected threat were assessed as well as skin conductance response as an objective psychophysiological measure. Patients with major depression showed impaired acquisition of conditioned fear. In addition, depressed patients showed impaired extinction of conditioned fear responses after successful fear conditioning. Generalization was not affected. However, there was no difference between patients with anxious and non-anxious depression. Results differed between objective and subjective measures. Our findings show altered fear acquisition and extinction in major depression as compared to healthy controls, but they do not favor differential fear learning and extinction mechanisms in the pathogenesis of anxious versus non-anxious depression. The results of impaired extinction warrant future studies addressing extinction learning elements in the treatment of depression.

2.
Brain Behav Immun ; 2021 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-33422640

RESUMO

Childhood trauma as well as severe events occurring later in life have been associated with the development of major depressive disorder (MDD). However, the interaction of early and later occurring adverse events in patients with MDD is understudied. This study aims to disentangle this interaction by investigating the effects on two of the main stress-response systems of the body, the hypothalamic-pituitaryadrenal (HPA-) axis and the immune system in depressed patients. The function of the HPA-axis was assessed by measuring FKBP5, SGK1 and NR3C1 mRNA-expression in peripheral blood after an in vivo glucocorticoid receptor (GR) challenge with 1.5 mg dexamethasone in 150 depressed in-patients (47.4% females). Childhood trauma was evaluated using the Childhood Trauma Questionnaire (CTQ), severe life events occurring one year prior to hospital admission were assessed with the List of Threatening Experiences (LTE). Multiple childhood traumata, i.e. ≥ 3, were present in 68 (45.5%) patients, 59 (39.3%) experienced ≥ 3 severe recent life events. The history of ≥ 3 severe recent life events was associated with an impaired GR-induction of SGK1 (F = 10.455; df = 1; p = 0.002) and FKBP5 mRNA expression (F = 8.720; df = 1; p = 0.004), and with elevated measures of the immune system such as CRP and lymphocyte count. In addition, severe recent life events were associated with a substantially impaired treatment response to antidepressants (F = 7.456; df = 1; p = 0.008). These effects could not be observed in relation to childhood trauma. Severe life events occurring prior to MDD development substantially impaired the stress-response systems and the response to treatment with antidepressants. This finding may indicate the need to employ additional treatment options such as psychotherapy right at the beginning of treatment or immune-modulating approaches.

3.
Eur Neuropsychopharmacol ; 44: 105-120, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33483252

RESUMO

There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety disorders. We investigated both categorical (symptom reduction of at least 50%) and dimensional outcomes from baseline to post-treatment and follow-up. Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder. No significant effects of 5-HTTLPR genotype on categorical or dimensional outcomes at post and follow-up were detected. We conclude that current evidence does not support the hypothesis of 5-HTTLPR as a moderator of treatment outcome for CBT in anxiety disorders. Future research should address whether other factors such as long-term changes or epigenetic processes may explain further variance in these complex gene-environment interactions and molecular-genetic pathways that may confer behavioral change following psychotherapy.

4.
Transl Psychiatry ; 11(1): 17, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33414402

RESUMO

Transcranial direct current stimulation (tDCS) is increasingly used as a form of noninvasive brain stimulation to treat psychiatric disorders; however, its mechanism of action remains unclear. Prolonged visual stimulation (PVS) can enhance evoked EEG potentials (visually evoked potentials, VEPs) and has been proposed as a tool to examine long-term potentiation (LTP) in humans. The objective of the current study was to induce and analyze VEP plasticity and examine whether tDCS could either modulate or mimic plasticity changes induced by PVS. Thirty-eight healthy participants received tDCS, PVS, either treatment combined or neither treatment, with stimulation sessions being separated by one week. One session consisted of a baseline VEP measurement, one stimulation block, and six test VEP measurements. For PVS, a checkerboard reversal pattern was presented, and for tDCS, a constant current of 1 mA was applied via each bioccipital anodal target electrode for 10 min (Fig. S1). Both stimulation types decreased amplitudes of C1 compared to no stimulation (F = 10.1; p = 0.002) and led to a significantly smaller increase (PVS) or even decrease (tDCS) in N1 compared to no stimulation (F = 4.7; p = 0.034). While all stimulation types increased P1 amplitudes, the linear mixed effects model did not detect a significant difference between active stimulation and no stimulation. Combined stimulation induced sustained plastic modulation of C1 and N1 but with a smaller effect size than what would be expected for an additive effect. The results demonstrate that tDCS can directly induce LTP-like plasticity in the human cortex and suggest a mechanism of action of tDCS relying on the restoration of dysregulated synaptic plasticity in psychiatric disorders such as depression and schizophrenia.

5.
J Psychiatr Res ; 132: 18-22, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33035761

RESUMO

Treatment resistance is common in obsessive-compulsive disorder (OCD) and associated with a significant burden for the individual patient. Accordingly, the identification of biomarkers as early predictors of the clinical response has become a central goal in the search for more efficacious and personalized treatments. Epigenetic mechanisms such as DNA methylation of the serotonin transporter gene (SLC6A4) have been suggested to predict therapy outcome in mental disorders closely related to OCD, but have not yet been investigated as such in OCD. The present therapy-epigenetic study therefore sought to address the potential role of SLC6A4 promoter methylation in the prediction of treatment response for the first time in OCD. Overall, 112 patients with primary OCD were investigated over the course of 8-10-week OCD-specific, cognitive behavioral therapy (CBT) comprising exposure and response prevention/management (phase I) and in vivo exposure exercises ('flooding', phase II). OCD symptoms were measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline as well as before and after the in vivo exposure phase. SLC6A4 promoter methylation at baseline was analyzed via pyrosequencing of sodium bisulfite-treated DNA extracted from blood cells. Lower baseline SLC6A4 promoter methylation predicted impaired treatment response (defined as reduction in Y-BOCS scores) in phase II (but not phase I) of CBT (ß = -0.359, p = .002). SLC6A4 methylation may thus constitute a potential early biomarker predicting biologically mediated clinical changes elicited specifically by exposure treatment. These results carry promise for clinical application and in the future could aid in early treatment modification and personalized treatment efforts.

6.
Psiquiatr. biol. (Internet) ; 27(3): 83-95, sept.-dic. 2020. tab, graf
Artigo em Espanhol | IBECS-Express | IBECS | ID: ibc-FGT-5852

RESUMO

OBJETIVO: La Monitorización Terapéutica de Drogas (llamada en inglés TDM: therapeutic drug monitoring) combina la cuantificación de las concentraciones de medicamentos en la sangre, la interpretación farmacológica y las directrices de tratamiento. La TDM introduce una herramienta de medicina de precisión en una ípoca de gran conciencia de la necesidad de tratamientos personalizados en neurología y psiquiatría. Las indicaciones claras de la TDM incluyen la ausencia de respuesta clínica en el rango de dosis terapéuticas, la evaluación de la adherencia farmacológica, problemas de tolerancia e interacciones medicamentosas. MÉTODOS: Basándose en la literatura existente, se describieron los rangos de referencia terapéutica recomendables, los valores críticos de laboratorio y los niveles de recomendación para usar la TDM para la optimización de dosis sin indicaciones específicas, se calcularon los factores de conversión, los factores para el cálculo de concentraciones medicamentosas relacionadas con la dosis (en inglés DRC dose-to-ratioconcentration) y el cociente entre el metabolito y el compuesto original (en inglés se llama MPR: metabolite-to-parent ratio). RESULTADOS: Este resumen de las guías actualizadas del consenso por la Task Force del TDM del Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie, ofrece el conocimiento práctico y teórico para la integración de la TDM como parte de la farmacoterapia con medicamentos neuropsiquiátricos en la práctica clínica rutinaria. CONCLUSIONES: La presente traducción en español, de la guía para la aplicación del TDM en medicamentos neuropsiquiátricos, tiene como objetivo ayudar a los clínicos a mejorar la seguridad y la eficacia de los tratamientos


OBJECTIVES: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation, and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalised treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities, and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues, and drug-drug interactions. METHODS: Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimisation without specific indications, conversion factors, factors for calculation of dose-related drug concentrations, and metabolite-to-parent ratios were calculated. RESULTS: This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuro- psychiatric agents into clinical routine. CONCLUSIONS: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment

7.
Fluids Barriers CNS ; 17(1): 67, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33176794

RESUMO

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.

8.
Int J Mol Sci ; 21(22)2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33203140

RESUMO

Complex neuropsychiatric-cardiac syndromes can be genetically determined. For the first time, the authors present a syndromal form of short QT syndrome in a 34-year-old German male patient with extracardiac features with predominant psychiatric manifestation, namely a severe form of secondary high-functioning autism spectrum disorder (ASD), along with affective and psychotic exacerbations, and severe dental enamel defects (with rapid wearing off his teeth) due to a heterozygous loss-of-function mutation in the CACNA1C gene (NM_000719.6: c.2399A > C; p.Lys800Thr). This mutation was found only once in control databases; the mutated lysine is located in the Cav1.2 calcium channel, is highly conserved during evolution, and is predicted to affect protein function by most pathogenicity prediction algorithms. L-type Cav1.2 calcium channels are widely expressed in the brain and heart. In the case presented, electrophysiological studies revealed a prominent reduction in the current amplitude without changes in the gating behavior of the Cav1.2 channel, most likely due to a trafficking defect. Due to the demonstrated loss of function, the p.Lys800Thr variant was finally classified as pathogenic (ACMG class 4 variant) and is likely to cause a newly described Cav1.2 channelopathy.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33007775

RESUMO

Preclinical evidence indicates that the endocannabinoid system is involved in neural responses to reward. This study aimed to investigate associations between basal serum concentrations of the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) with brain functional reward processing. Additionally, a personality measure of reward dependence was obtained. Brain functional data were obtained of 30 right-handed adults by conducting fMRI at 3 Tesla using a reward paradigm. Reward dependence was obtained using the subscale reward dependence of the Tridimensional Personality Questionnaire (TPQ). Basal concentrations of AEA and 2-AG were determined in serum. Analyzing the fMRI data, for AEA and 2-AG ANCOVAs were calculated using a full factorial model, with condition (reward > control, loss > control) and concentrations for AEA and 2-AG as factors. Regression analyses were conducted for AEA and 2-AG on TPQ-RD scores. A whole-brain analysis showed a significant interaction effect of AEA concentration by condition (positive vs. negative) within the putamen (x = 26, y = 16, z = -8, F13.51, TFCE(1, 54) = 771.68, k = 70, PFWE = 0.044) resulting from a positive association of basal AEA concentrations and putamen activity to rewarding stimuli, while this association was absent in the loss condition. AEA concentrations were significantly negatively correlated with TPQ reward dependence scores (rspearman = -0.56, P = 0.001). These results show that circulating AEA may modulate brain activation during reward feedback and that the personality measure reward dependence is correlated with AEA concentrations in healthy human volunteers. Future research is needed to further characterize the nature of the lipids' influence on reward processing, the impact on reward anticipation and outcome, and on vulnerability for psychiatric disorders.

10.
Depress Anxiety ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33058370

RESUMO

BACKGROUND: Previous work on gene-environment (GxE) interplay concerning anxiety has focused on the interaction of 5-HTTLPR with childhood adversities or traumatic events whereas the impact of recent stressors is understudied, as is the integration of resilience. The current study aimed to investigate the interactive effect of 5-HTTLPR and recent stress on anxiety in adolescents considering resilience as buffer of a GxE risk constellation. METHOD: In a random population-based sample of 14-21 years old from Dresden, Germany, (N = 1180; genotyped = 942) recent stress (Daily Hassles [DH] Scale, Perceived Stress Scale, Screening Scale of the Trier Inventory for the Assessment of Chronic Stress), resilience (Connor-Davidson resilience scale) and anxiety (Patient Reported Outcome Measurement Information System Anxiety Short Form) were assessed via questionnaire in 2015 or 2016. RESULTS: Fractional regression models revealed that resilience interacted with recent stress in form of DH as well as recent chronic stress and 5-HTTLPR regarding anxiety. Participants carrying the more active LA LA genotype reported consistently higher levels of anxiety when experiencing more DH or more recent chronic stress and having low levels of resilience. When the resilience scores were high, LA LA carriers reported the lowest anxiety scores despite DH or recent chronic stress. CONCLUSION: Findings revealed an interactive relationship between 5-HTTLPR genotype and recent stress suggesting resilience to function as an additional dimension buffering the impact of a GxE risk constellation. Early interventions to build resilience may be useful to prevent an escalation of distress and associated unfavorable health outcomes.

11.
J Affect Disord ; 277: 531-539, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32889377

RESUMO

BACKGROUND: 5-HTTLPR/rs25531 is suspected to be involved in the pathogenesis of both coronary heart disease (CHD)1 and depression. We aimed to investigate the role of 5-HTTLPR/rs25531 in the development of depressive symptoms among CHD patients in a longitudinal design. METHODS: N = 265 participants with CHD diagnosis were included while hospitalized in a department of cardiology and genotyped for the 5-HTTLPR/rs25531. Depressive symptoms were measured using the Patient Health Questionnaire (PHQ-9)7 at baseline and after 6 and 12 months. Binary logistic regression models were used to analyze the association of 5-HTTLPR/rs25531 with the prevalence of depressive symptoms at each time point as well as with the incidence and persistence of depressive symptoms at follow-up. RESULTS: "LALA" genotype was associated with a higher prevalence of depressive symptoms 12 months after study inclusion. "LALA" genotype was associated with a higher incidence of depressive symptoms 6 and 12 months after study inclusion. There was no association of 5-HTTLPR/rs25531 with the persistence of depressive symptoms. LIMITATIONS: Inclusion criteria did not demand a particular cardiac event at baseline, which aggravated the interpretation of the time-specific results. The majority of the participants was of male gender which could cause bias. The present study only vaguely differentiated between ethnical groups which might cause bias regarding nationality-dependent allele distributions. CONCLUSION: The present study suggests a time-dependent association of the "LALA" genotype with depressive symptoms in CHD patients. 5-HTTLPR/rs25531 might be an important marker to detect risk groups for later onset depressive symptoms among CHD patients.

12.
Psychol Med ; : 1-12, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32892761

RESUMO

BACKGROUND: Autoimmune encephalitis (AE) is an important consideration during the diagnostic work-up of secondary mental disorders. Indeed, isolated psychiatric syndromes have been described in case reports of patients with underlying AE. Therefore, the authors performed a systematic literature review of published cases with AE that have predominant psychiatric/neurocognitive manifestations. The aim of this paper is to present the clinical characteristics of these patients. METHODS: The authors conducted a systematic Medline search via Ovid, looking for case reports/series of AEs with antineuronal autoantibodies (Abs) against cell surface/intracellular antigens combined with predominant psychiatric/neurocognitive syndromes. The same was done for patients with Hashimoto encephalopathy/SREAT. Only patients with signs of immunological brain involvement or tumors in their diagnostic investigations or improvement under immunomodulatory drugs were included. RESULTS: We identified 145 patients with AE mimicking predominant psychiatric/neurocognitive syndromes. Of these cases, 64% were female, and the mean age among all patients was 43.9 (±22.1) years. Most of the patients had Abs against neuronal cell surface antigens (55%), most frequently against the NMDA-receptor (N = 46). Amnestic/dementia-like (39%) and schizophreniform (34%) syndromes were the most frequently reported. Cerebrospinal fluid changes were found in 78%, electroencephalography abnormalities in 61%, and magnetic resonance imaging pathologies in 51% of the patients. Immunomodulatory treatment was performed in 87% of the cases, and 94% of the patients responded to treatment. CONCLUSIONS: Our findings indicate that AEs can mimic predominant psychiatric and neurocognitive disorders, such as schizophreniform psychoses or neurodegenerative dementia, and that affected patients can be treated successfully with immunomodulatory drugs.

13.
Psychother Psychosom ; : 1-7, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32920561

RESUMO

INTRODUCTION: Obsessive-compulsive disorder (OCD) is associated with high chronicity and treatment resistance, indicating the need for early therapy response markers enabling fast and personalized treatment adaptations. Although epigenetic mechanisms such as DNA methylation of the oxytocin receptor (OXTR) gene have previously been linked to OCD pathogenesis, epigenetic markers as predictors of treatment success have not yet been investigated in OCD. OBJECTIVE: For the first time, this therapyepigenetic study aimed to investigate the role of OXTR methylation as a treatment response marker in OCD. METHODS: In total, 113 inpatients with OCD (57 females) were compared to 113 age- and sex-matched healthy controls. Patients were investigated over a 10-week course of standardized, OCD-specific cognitive-behavioral psychotherapy. Clinical response was measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline, before in vivo exposure, and after therapy. OXTR exon III methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. RESULTS: Relative OXTR hypermethylation was observed in OCD patients compared to healthy controls. In OCD, higher baseline OXTR methylation was found to predict impaired treatment response at both categorical (responders vs. nonresponders) and dimensional (relative Y-BOCS reduction) levels, whereas lower baseline methylation was related to treatment response and greater symptom improvements. Analysis of Y-BOCS subdimensions revealed that the association between OXTR hypermethylation with impaired treatment response applied especially to symptoms related to obsessions, but not compulsions. CONCLUSIONS: OXTR hypermethylation may constitute a predictive marker of impaired treatment response in OCD and thus carries great potential for future personalized treatment efforts in OCD.

14.
Front Psychiatry ; 11: 745, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32922313

RESUMO

Background: In a subgroup of patients with mood disorders, clear-cut organic disorders are responsible for depressive symptoms (e.g., autoimmune diseases such as multiple sclerosis or systemic lupus erythematosus). In these cases, an organic affective disorder can be diagnosed. Case Presentation: The authors present the case of a 59-year-old male patient who developed a severe depressive episode over approximately 6 months and was, therefore, admitted to the hospital. In retrospect, he reported that, at age 39, he suffered from self-limiting sensory disturbances and muscle weakness in both legs. The current magnetic resonance imaging of his brain showed several conspicuous FLAIR-hyperintense supratentorial white matter lesions compatible with chronic inflammatory brain disease. Imaging of the spinal axis revealed no clear spinal lesions. Cerebrospinal fluid (CSF) analyses showed CSF-specific oligoclonal bands. Therefore, multiple sclerosis was diagnosed. Further CSF analyses, using tissue-based assays with indirect immunofluorescence on unfixed murine brain tissue, revealed a (peri-)nuclear signal and a strong neuritic signal of many neurons, especially on granule cells in the cerebellum, hippocampus, and olfactory bulb, as well as in the corpus callosum. Additionally, antinuclear antibody (ANA) titers of 1:12,800 and a lymphopenia were detected in blood tests. Further system clarification showed no suspicion of rheumatic or oncological disease. Anti-inflammatory treatment led to rapid and sustained improvement. Conclusion: The present patient suffered from a probable "autoimmune depression" in the context of newly diagnosed multiple sclerosis with typical MRI and CSF pathologies, alongside mild concomitant latent systemic autoimmune process (with high-titer ANAs and lymphopenia) and unknown antineuronal antibodies. The case report illustrates that a depressive syndrome suggestive of primary idiopathic depressive disorder may be associated with an autoimmune brain involvement. The detection of such organic affective disorders is of high clinical relevance for affected patients, as it enables alternative and more causal treatment approaches.

15.
Compr Psychiatry ; 102: 152196, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32927367

RESUMO

INTRODUCTION: Unipolar depression is a common and debilitating disorder. Immunological explanatory approaches have become increasingly important in recent years and can be studied particularly well in the cerebrospinal fluid (CSF). Previous studies discerned alterations in interleukin (IL)-6 and IL-8 levels; however, findings regarding IL-8 were partly contradictory. The aim of the present study was to investigate the concentrations of different cytokines and chemokines, focusing on IL-8, in the CSF of patients with unipolar depression. MATERIALS AND METHODS: Participants included 40 patients with unipolar depression and 39 mentally healthy controls with idiopathic intracranial hypertension. CSF cytokine levels were measured using a magnetic bead multiplexing immunoassay. RESULTS: IL-8 levels in the CSF of the patient group with depression were significantly higher than those in the control group (Mean ± SD: 38.44 ± 6.26 pg/ml versus 21.40 ± 7.96 pg/ml; p < .001). LIMITATIONS: The significance of the results is limited by the retrospective design and methodological aspects. DISCUSSION: The main findings of this study were significantly higher concentrations of IL-8 in the CSF of patients with unipolar depression than in the control group. The detection of high CSF IL-8 levels in this study supports the idea that inflammatory processes might play a role in the pathophysiology of a subgroup of patients with depression.

16.
Diagnostics (Basel) ; 10(9)2020 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-32937787

RESUMO

Introduction: Secondary schizophrenia spectrum disorders (SSDs) have clearly identifiable causes. The Department for Psychiatry and Psychotherapy at the University Hospital Freiburg has continued to expand its screening practices to clarify the organic causes of SSDs. This retrospective analysis was carried out to analyze whether a comprehensive organic diagnostic procedure could be informative in patients with SSDs. Methods and Participants: The "Freiburg Diagnostic Protocol in Psychosis" (FDPP) included basic laboratory analyses (e.g., thyroid hormones), metabolic markers, pathogens, vitamin status, different serological autoantibodies, rheumatic/immunological markers (e.g., complement factors), cerebrospinal fluid (CSF) basic and antineuronal antibody analyses, as well as cranial magnetic resonance imaging (cMRI) and electroencephalography (EEG). The findings of 76 consecutive patients with SSDs (55 with paranoid-hallucinatory; 14 with schizoaffective; 4 with hebephrenic; and 1 each with catatonic, acute polymorphic psychotic, and substance-induced psychotic syndromes) were analyzed. Results: Overall, vitamin and trace element deficiency was identified in 92%. Complement factor analyses detected reduced C3 levels in 11%. Immunological laboratory alterations were detected in 76%. CSF analysis revealed general alterations in 54% of the patients, mostly with signs of blood-brain barrier dysfunction. cMRI analyses showed chronic inflammatory lesions in 4%. Combination of EEG, cMRI, and CSF revealed alterations in 76% of the patients. In three patients, autoimmune psychosis was suspected (4%). Discussion: On the basis of these findings, we conclude that a comprehensive diagnostic procedure according to the FDPP in patients with SSD is worthwhile, considering the detection of secondary, organic forms of SSDs, as well as alterations in "modulating factors" of the disease course, such as vitamin deficiency. Larger studies using comprehensive diagnostic protocols are warranted to further validate this approach.

17.
Front Psychiatry ; 11: 627, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848899

RESUMO

Background: Autoimmune encephalitis, such as anti-NMDA-receptor encephalitis, typically presenting with subacute onset of neuropsychiatric symptoms, can be detected by antineuronal autoantibodies or inflammatory changes in the cerebrospinal fluid (CSF), as well as pathological alterations in electroencephalography (EEG), magnetic resonance imaging (MRI), or [18F]fluorodeoxyglucose positron emission tomography (FDG PET). For patients with predominant psychotic symptoms, the term autoimmune psychosis was proposed. Here, the authors present the case of a patient with probable autoimmune psychosis associated with unknown antineuronal antibodies. Case Presentation: A 18-year-old male patient with preexisting autism spectrum disorder developed a severe catatonic syndrome over 2.5 years. The MRI showed normal findings, the EEG depicted intermittent slowing, and the independent component analyses showed additional sharp spikes. However, FDG PET, the basic laboratory analysis and testing of the serum/CSF for well-characterized antineuronal autoantibodies were unsuspicious. The serum and CSF "tissue-based assay" using indirect immunofluorescence on unfixed murine brain tissue revealed antineuronal autoantibodies against an unknown epitope in granule cells in the cerebellum and to neurites of hippocampal interneurons with a somatodendritic staining pattern. The immunosuppressive treatment with high-dose glucocorticoids, plasma exchange, and rituximab led to partial improvement. Conclusion: The patient probably suffered from autoantibody-associated autoimmune psychosis. The special features of the case were that the patient (1) presented with mostly inconspicuous basic diagnostics, except for the altered EEG in combination with the detection of CSF autoantibodies directed against a currently unknown epitope, (2) experienced an isolated and long-lasting psychotic course, and (3) had pre-existing autism spectrum disorder. The detection of a probable autoimmune pathophysiology in such cases seems important, as it offers new and more causal immunosuppressive treatment alternatives.

18.
J Neural Transm (Vienna) ; 127(12): 1651-1662, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32860562

RESUMO

Depression and coronary heart disease (CHD) are prevalent and often co-occurring disorders. Both have been associated with a dysregulated stress system. As a central element of the stress system, the FKBP5 gene has been shown to be associated with depression. In a prospective design, this study aims to investigate the association of FKBP5 with depressive symptoms in CHD patients. N = 268 hospitalized CHD patients were included. Depressive symptoms were measured using the Hospital Anxiety and Depression Scale (HADS-D) at four time points (baseline, and after 1 month, 6 months, and 12 months). The functional FKBP5 single-nucleotide polymorphism (SNP) rs1360780 was selected for genotyping. Linear regression models showed that a higher number of FKBP5 C alleles was associated with more depressive symptoms in CHD patients both at baseline (p = 0.015) and at 12-months follow-up (p = 0.025) after adjustment for confounders. Further analyses revealed that this effect was driven by an interaction of FKBP5 genotype with patients' prior CHD course. Specifically, only in patients with a prior myocardial infarction or coronary revascularization, more depressive symptoms were associated with a higher number of C alleles (baseline: p = 0.046; 1-month: p = 0.026; 6-months: p = 0.028). Moreover, a higher number of C alleles was significantly related to a greater risk for dyslipidemia (p = .016). Our results point to a relevance of FKBP5 in the association of the two stress-related diseases depression and CHD.

19.
Transl Psychiatry ; 10(1): 279, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32782247

RESUMO

The central role played by cerebrospinal-fluid (CSF) examinations including antineuronal autoantibody (Ab) testing is increasingly recognized in psychiatry. The rationale of this study was to present a multimodally investigated group of patients. In total, 992 patients were analyzed for CSF alterations: 456 patients with schizophreniform and 536 with affective syndromes. Ab measurement included testing for established antineuronal IgG-Abs against intracellular antigens in serum (Yo/Hu/Ri/cv2[CRMP5]/Ma1/Ma2/SOX1/TR[DNER]/Zic4/amphiphysin/GAD65) and for cell surface antigens in the CSF (NMDAR/AMPA-1/2-R/GABA-B-R/LGI1/CASPR2/DPPX). In 30 patients with "red flags" for autoimmune psychosis, "tissue tests" were performed. Additional diagnostics included MRI and EEG analyses. CSF white-blood-cell counts were increased in 4% and IgG indices in 2%; CSF-specific oligoclonal bands were detected in 4%; overall, 8% displayed signs of neuroinflammation. In addition, 18% revealed increased albumin quotients. Antineuronal Abs against intracellular antigens were detected in serum in 0.6%. Antineuronal Abs against established cell surface antigens were detected in serum of 1% and in the CSF of 0.3% (CSF samples were only questionably positive). Abnormal IgG binding in "tissue tests" was detected in serum of 23% and in CSF of 27%. In total, 92% of the Ab-positive patients demonstrated at least one sign of brain involvement in additional diagnostics using CSF, MRI, EEG, and FDG-PET. In summary, CSF basic analyses revealed signs of blood-brain-barrier dysfunction and neuroinflammation in relevant subgroups of patients. Established antineuronal IgG-Abs were rare in serum and even rarer in the CSF. "Tissue tests" revealed frequent occurrences of Ab-binding; therefore, novel antineuronal Abs could play a relevant role in psychiatry.

20.
Lancet Psychiatry ; 7(9): 801-812, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32828168

RESUMO

Persistent depressive disorder is a chronic mood disorder that is common and often more disabling than episodic major depression. In DSM-5, the term subsumes several chronic depressive presentations, including dysthymia with or without superimposed major depressive episodes, chronic major depression, and recurrent major depression without recovery between episodes. Dysthymia can be difficult to detect in psychiatric and primary care settings until it intensifies in the form of a superimposed major depressive episode. Although information is scarce concerning the cause of persistent depressive disorder including dysthymia, the causation is likely to be multifactorial. In this narrative Review, we discuss current knowledge about the nosology and neurobiological basis of dysthymia and persistent depressive disorder, emphasising a dimensional perspective based on course for further research. We also review new developments in psychotherapy and pharmacotherapy for persistent depressive disorder, and propose a tailored, modular approach to accommodate its multifaceted nature.


Assuntos
Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/terapia , Transtorno Distímico/diagnóstico , Transtorno Distímico/terapia , Antidepressivos/uso terapêutico , Doença Crônica , Terapia Combinada , Comorbidade , Transtorno Depressivo Maior/epidemiologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Transtorno Distímico/epidemiologia , Humanos , Psicoterapia/métodos , Recidiva
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