Biomarkers in Neuropsychiatry最新文献

Background

Little is known whether cholesterol levels affect depression treatment outcomes. We aimed to study the association between baseline and changes in blood cholesterol levels with drug-specific antidepressant response and long-term prognosis in patients with major depressive disorder (MDD).

Methods

From the Danish site of the GENDEP trial, we included patients with MDD randomized to escitalopram or nortriptyline treatment. Total and free cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and depression severity using the Montgomery-Åsberg Depression rating scale (MADRS) were measured at baseline and after 26 weeks of treatment initiation. By linkage with nationwide registers, we analyzed psychiatric and cardiometabolic hospital contacts during the five years after the trial. We assessed the association of cholesterol levels with a) depression severity using linear and mixed effects regression analyses; and b) the register-based outcomes using Cox regression analyses.

Results

Among 78 patients (mean age 38 years, 74% women, mean MADRS score 28 [SD=4.5]), baseline cholesterol levels were not correlated with antidepressant response. Among 58 patients with measurements at week 0 and 26, cholesterol levels significantly increased in both treatment groups. Only in patients using escitalopram did the increase in total and free cholesterol and LDL correlate with improved antidepressant response. Baseline or changes in cholesterol were not associated with 5-year outcomes.

Limitations

Secondary analyses on a rather small sample.

Conclusion

This study provides clinical insight into potential drug-specific associations between increases in cholesterol levels and antidepressant response to escitalopram but not nortriptyline.

The recent discovery of innate lymphoid cells (ILCs) has provided new insights into our understanding of the pathogenesis of many disease conditions with immune dysregulation. Type 1 innate lymphoid cells (ILC1s) induce type I immunity and are characterized by the expression of signature cytokine IFN-γ and the master transcription factor T-bet; ILC2s stimulate type II immune responses and are defined by the expression of signature cytokines IL-5 and IL-13, and transcription factors ROR-α and GATA3; ILC3s requires the transcription factor RORγt and produce IL-22 and IL-17. ILCs are largely tissue-resident and are enriched at barrier surfaces of the mammalian body. Increasing evidence shows that inflammation is involved in the pathogenesis of depression. Although few studies have directly investigated the role of ILCs in depression, several studies have examined the levels of cytokines produced by ILCs in depressed subjects. This review summarizes the potential roles of ILCs in depression. A better understanding of the biology of ILCs may lead to the development of new therapeutic strategies for the management of depression.

Patients with schizophrenia have impairments in early auditory system functioning that relate to clinical, cognitive, and psychosocial functioning. Some neurophysiological biomarkers of auditory information processing are sensitive to and predictive of clinically relevant outcomes following auditory-based targeted cognitive training (TCT) in schizophrenia. It is not known, however, whether schizophrenia patients show abnormalities at the earliest stage of sensory processing reflecting the integrity of the ascending auditory pathway at the level of the brainstem, or whether such abnormalities can serve as biomarkers. This study aimed to determine whether click-evoked auditory brainstem responses (click ABRs) are 1) abnormal in schizophrenia patients relative to healthy comparison subjects (HCS), 2) acutely sensitive to or predictive of TCT response, and 3) associated with clinically relevant symptoms. We also sought to determine whether 4) click ABRs show adequate psychometric reliability. Click ABRs were examined in 52 patients with schizophrenia and 32 HCS. Patients were randomized to either TCT (n = 30), which comprised 30 h of training, or treatment as usual (TAU; n = 23). Patients showed intact click ABRs relative to HCS and click ABRs did not change significantly after 1 or 30 h of TCT. Exploratory analyses revealed modest relationships between click ABRs and baseline measures of positive symptoms and speech-in-noise perception; acute changes in ABRs were modestly related to improvements on measures of cognition independent of treatment. ABR measurements showed adequate internal consistency indicating their suitability for cross-sectional studies of individual differences, but poor test-retest reliability indicating poor suitability for clinical trials. In contrast to a growing literature demonstrating the utility of later cortical neurophysiological measures for translational research, the present findings indicate that brainstem-mediated responses are intact in schizophrenia and are not sensitive to or predictive of clinical changes in the context of TCT. These data provide guidance for establishing future neurophysiology-guided interventions in schizophrenia.

Background

Understanding how treatments change neurobiology is critical to developing predictors of treatment response. This is especially true for anxiety disorders—the most common psychiatric disorders across the lifespan. With this in mind, we examined neurofunctional predictors of treatment response and neurofunctional changes associated with treatment across anxiety disorders.

Methods

PubMed/Medline was searched for prospective treatment studies that included parallel examinations of functional activation or connectivity (both task-based and resting state) in adults and youth with panic disorder and generalized, separation, and/or social anxiety disorders published before April 30, 2021. All studies examining baseline predictors or changes related to pharmacologic and psychotherapeutic treatment of DSM-IV and DSM-5 anxiety disorders were included. Demographic, clinical, and treatment data as well as neurofunctional outcomes were extracted and summarized.

Results

Twenty-nine studies examined changes in functional activation and/or connectivity (56 treatment arms) related to treatment and twenty-three examined neurofunctional predictors of treatment response. Predictors of treatment response and treatment-related neurofunctional changes were frequently observed within amygdala-prefrontal circuits. However, immense heterogeneity and few replication studies preclude a cohesive neurofunctional treatment response model across anxiety disorders.

Conclusions

The extant literature describing neurofunctional aspects of treatment response in anxiety disorders is best viewed as a partially constructed scaffold on which to build a clinically translatable set of robust neuroimaging biomarkers that can be used to guide treatment and to select from available treatment. The construction of this understanding will require harmonization of analytic and task approaches, larger samples, and replication of component studies.

The serious mental illness (SMI) phenotype is marked by several different symptom domains and biomedical challenges. The nature of SMI renders in-person assessment challenging, due to problems in event recall, response biases, lack of experience in real-world functional domains, and difficulties identifying informants. Digital strategies offer a promising alternative to in-person assessments and allow for remote delivery of cognitive and social cognitive assessments in addition to continuous momentary assessment of activities, moods, symptoms, expressions, experiences, and psychophysiological variables. Remote assessments of mood, emotion, behavior, cognition, and self-assessment have been successfully collected across various SMI conditions. Both active (paging and triggered observations of facial and vocal expressions) and passive (global positioning, actigraphy) methods have been deployed remotely, similarly to in-person assessments previously conducted in the laboratory. Advanced strategies in data analysis are used to examine this information and to guide the development of newer advances in assessment of phenotypic variation in SMI.

Clozapine, a drug effective in treatment resistant schizophrenia, can modulate the brain’s electrical activity as measured by an electroencephalogram (EEG). Past reviews have focused on synthesizing literature related to epileptiform activity or rate of seizures in clozapine treated individuals. The aim of this review was to determine whether clozapine’s mediated effects on measurements related to neural oscillations can inform its therapeutic effects. Here, literature pertaining to studies that implemented pre-post designed investigations of clozapine and measured frequency characteristics of neural oscillations in individuals with schizophrenia were reviewed. The synthesis of findings suggests that while clozapine is associated with alterations in all neural oscillations, slower waves (delta and theta) are consistently increased in power by clozapine. We then further discuss potential mechanisms that may underlie these effects of clozapine. Future research can implement the findings of this review to motivate hypothesis-driven investigations into clozapine responsiveness biomarkers.

The predictive coding theory of psychosis posits that individuals with schizophrenia demonstrate abnormalities in the strength of top-down modulation (based on prior experience) of sensory signals. Evidence suggests that difficulty perceiving depth inversion illusions (DIIs) (i.e., more accurate perception of stimuli under conditions in which control subjects perceive these illusions) may reflect this abnormality in people with schizophrenia. This review synthesizes findings from all studies that have investigated DII perception in schizophrenia, high-risk syndromes, and conditions associated with risk for psychosis outside of a psychotic disorder such as those involving cannabis use, alcohol intoxication and withdrawal, and sleep deprivation. Cognitive and biological mechanisms contributing to DII resistance, and strengths and confounds of using the DII task as a measure of predictive coding are also discussed. The available evidence indicates that psychosis is associated with resistance to DIIs, whereas schizophrenia in the absence of active psychosis is less strongly associated with this effect. This may be due to psychosis-related deficiencies in top-down signaling and a compensatory overreliance on bottom-up signaling. Overall, the evidence reviewed suggests that the DII task is a sensitive measure of predictive coding in schizophrenia that could be used as a visual biomarker to predict risk and impending changes in clinical state within the disorder. Additional studies that measure changes longitudinally are necessary to further explore the possibility of using the DII task as a visual biomarker for psychosis in clinical settings.

Background

Major depressive disorder (MDD) presents with both peripheral and central alterations, such that crosstalk between the periphery and the central nervous system could contribute to its aetio-pathophysiology. One putative mediating mechanism is circulating extracellular vesicles (EVs) and their microRNA (miRNA) cargo. In this study, we investigated differential expression of the serum EV miRNome in MDD patients versus controls with the aims of identifying potential EV miRNA biomarkers and downstream target gene pathways.

Methods

miRNA-Sequencing was performed on serum EVs isolated from MDD patients (n = 42) and matched healthy Controls (n = 18). Differential expression analysis was conducted, followed by diagnostic power analysis of dysregulated EV miRNAs, and pathway analysis of their target genes.

Results

Of 1800 serum EV miRNAs detected consistently, 33 were differentially expressed in MDD and Control subjects, 17 up-regulated and 16 down-regulated. Receiver-operating characteristic analysis identified an up-regulated and a down-regulated panel of EV miRNAs, each with additive diagnostic power as a differential biomarker for MDD. Predicted target gene-pathways were significantly enriched with respect to brain function, signal transduction and substance dependence ontology.

Conclusions

This study provides one of the first reports of dysregulation of the peripheral EV miRNome in MDD, including evidence for EV miRNAs as potential MDD biomarkers and identification of pathways via which they may contribute to MDD pathophysiology. Large-scale studies are required to confirm EV miRNome biomarker potential in MDD. Empirical evidence for involvement of the dysregulated EV miRNAs in the predicted target-gene pathways relevant to MDD pathophysiology is required.