Neuropathology Of Depression Research Articles

Changes of structural functional connectivity coupling and its correlations with cognitive function in patients with major depressive disorder

BackgroundPrevious neuroimaging studies have reported structural and functional brain abnormalities in major depressive disorder (MDD). This study aimed to explore whether the coherence of structural-functional networks was affected by disease and investigate its correlation with clinical manifestations. MethodsThe severity of symptoms and cognitive function of 121 MDD patients and 139 healthy controls (HC) were assessed, and imaging data, including diffusion tensor imaging, T1 structural magnetic resonance imaging (MRI) and resting-state functional MRI, were collected. Spearman correlation coefficients of Kullback–Leibler similarity (KLS), fiber number (FN), fractional anisotropy (FA) and functional connectivity (FC) were calculated as coupling coefficients. Double-weight median correlation analysis was conducted to investigate the correlations between differences in brain networks and clinical assessments. ResultsThe percentage of total correct response of delayed matching to sample and the percentage of delayed correct response of pattern recognition memory was lower in MDD. Compared with the HC, KLS-FC coupling between the parietal lobe and subcortical area, FA-FC coupling between the temporal and parietal lobe, and FN-FC coupling in the frontal lobe was lower in MDD. Several correlations between structural-functional connectivity and clinical manifestations were identified. LimitationsFirst, our study lacks longitudinal follow-up data. Second, the sample size was relatively small. Moreover, we only used the Anatomical Automatic Labeling template to construct the brain network. Finally, the validation of the causal relationship of neuroimaging-behavior factors was still insufficient. ConclusionsThe alternation in structural-functional coupling were related to clinical characterization and might be involved in the neuropathology of depression.

Disrupted functional connectivity of the cerebellum with default mode and frontoparietal networks in young adults with major depressive disorder

Cerebellar dysconnectivity has repeatedly been documented in major depressive disorder (MDD). The cerebellum is composed of multiple functionally distinct subunits, and whether those subunits show similar or distinct dysconnectivity patterns with the cerebrum in MDD, is still unclear and needs to be further clarified. In this study, 91 MDD patients (23 male and 68 female) and 59 demographically matched healthy controls (22 male and 37 female) were enrolled to explore the cerebellar-cerebral dysconnectivity pattern in MDD by using the cutting-edge cerebellar partition atlas. Results showed that MDD patients exhibit decreased cerebellar connectivity with cerebral regions of default mode (DMN), frontoparietal networks (FPN), and visual areas. The dysconnectivity pattern was statistically similar across cerebellar subunits, with no significant diagnosis-by-subunit interactions. Correlation analyzes showed that cerebellar-dorsal lateral prefrontal cortex (DLPFC) connectivity is significantly correlated with anhedonia in MDD patients. Such dysconnectivity pattern was not affected by sex, which, however, should be further replicated in larger samples. These findings suggest a generalized disrupted cerebellar-cerebral connectivity pattern in MDD across all cerebellar subunits, which partially accounts for depressive symptoms in MDD, thus highlighting the pivotal role of the disrupted connectivity of cerebellum with DMN and FPN in the neuropathology of depression.

Resting-state functional connectome predicts individual differences in depression during COVID-19 pandemic.

Stressful life events are significant risk factors for depression, and increases in depressive symptoms have been observed during the COVID-19 pandemic. The aim of this study is to explore the neural makers for individuals' depression during COVID-19, using connectome-based predictive modeling (CPM). Then we tested whether these neural markers could be used to identify groups at high/low risk for depression with a longitudinal dataset. The results suggested that the high-risk group demonstrated a higher level and increment of depression during the pandemic, as compared to the low-risk group. Furthermore, a support vector machine (SVM) algorithm was used to discriminate major depression disorder patients and healthy controls, using neural features defined by CPM. The results confirmed the CPM's ability for capturing the depression-related patterns with individuals' resting-state functional connectivity signature. The exploration for the anatomy of these functional connectivity features emphasized the role of an emotion-regulation circuit and an interoception circuit in the neuropathology of depression. In summary, the present study augments current understanding of potential pathological mechanisms underlying depression during an acute and unpredictable life-threatening event and suggests that resting-state functional connectivity may provide potential effective neural markers for identifying susceptible populations. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Resolving heterogeneity in depression using individualized structural covariance network analysis.

Elucidating individual aberrance is a critical first step toward precision medicine for heterogeneous disorders such as depression. The neuropathology of depression is related to abnormal inter-regional structural covariance indicating a brain maturational disruption. However, most studies focus on group-level structural covariance aberrance and ignore the interindividual heterogeneity. For that reason, we aimed to identify individualized structural covariance aberrance with the help of individualized differential structural covariance network (IDSCN) analysis. T1-weighted anatomical images of 195 first-episode untreated patients with depression and matched healthy controls (n = 78) were acquired. We obtained IDSCN for each patient and identified subtypes of depression based on shared differential edges. As a result, patients with depression demonstrated tremendous heterogeneity in the distribution of differential structural covariance edges. Despite this heterogeneity, altered edges within subcortical-cerebellum network were often shared by most of the patients. Two robust neuroanatomical subtypes were identified. Specifically, patients in subtype 1 often shared decreased motor network-related edges. Patients in subtype 2 often shared decreased subcortical-cerebellum network-related edges. Functional annotation further revealed that differential edges in subtype 2 were mainly implicated in reward/motivation-related functional terms. In conclusion, we investigated individualized differential structural covariance and identified that decreased edges within subcortical-cerebellum network are often shared by patients with depression. The identified two subtypes provide new insights into taxonomy and facilitate potential clues to precision diagnosis and treatment of depression.

Neuropathology of depression in non-demented older adults: A large postmortem study of 741 individuals

Associations between age-related neuropathological lesions and adult-onset lifetime major depressive disorder (a-MDD), late-life MDD (LLD), or depressive symptoms close to death (DS) were examined in a large community sample of non-demented older adults. Seven hundred forty-one individuals (age at death = 72.2 ± 11.7 years) from the Biobank for Aging Studies were analyzed. a-MDD was present in 54 (7.3%) participants, LLD in 80 (10.8%), and DS in 168 (22.7%). After adjustment for covariates and compared to controls, a-MDD, LDD and DS were associated with small vessel disease (p = 0.039, p = 0.003, and p = 0.003 respectively); LLD, and DS were associated with brain infarcts (p = 0.012, p = 0.018, respectively) and Lewy body disease (p = 0.043, p = 0.002, respectively). DS was associated with beta-amyloid plaque burden (p = 0.027) and cerebral amyloid angiopathy (p = 0.035) in cognitively normal individuals (Clinical Dementia Rating scale = 0). Vascular brain pathology was the strongest correlate of clinical depictions of depression in the absence of dementia, corroborating the vascular hypothesis of depression. Lewy body pathology underlay DS. An older adult with DS or LLD should be monitored for possible cognitive decline or neurodegenerative disorders.

The Role of MicroRNA and Microbiota in Depression and Anxiety.

Depression and anxiety are devastating disorders. Understanding the mechanisms that underlie the development of depression and anxiety can provide new hints on novel treatments and preventive strategies. Here, we summarize the latest findings reporting the novel roles of gut microbiota and microRNAs (miRNAs) in the pathophysiology of depression and anxiety. The crosstalk between gut microbiota and the brain has been reported to contribute to these pathologies. It is currently known that some miRNAs can regulate bacterial growth and gene transcription while also modulate the gut microbiota composition, suggesting the importance of miRNAs in gut and brain health. Treatment and prevention strategies for neuropsychiatric diseases, such as physical exercise, diet, and probiotics, can modulate the gut microbiota composition and miRNAs expressions. Nonetheless, there are critical questions to be addressed to understand further the mechanisms involved in the interaction between the gut microbiota and miRNAs in the brain. This review summarizes the recent findings of the potential roles of microbiota and miRNA on the neuropathology of depression and anxiety, and its potential as treatment strategies.

Ninjinyoeito exerts an antidepressant‐like effect by enhancing the central noradrenergic system

ABSTRACTAimNinjinyoeito (NYT) is a Kampo medicine prescribed for patients with decreased mental and physical energy. Clinical studies demonstrate that NYT ameliorates depressive symptoms in patients with various diseases. However, the underlying therapeutic mechanisms of action remain unclear. The monoaminergic system has been implicated in the neuropathology of depression. Using immobility in the tail suspension test to evaluate depression‐like behavior, we aimed to examine the effects of NYT and the involvement of the α1‐adrenoceptor and serotonin (5‐HT)1A receptor in its mechanism of action.MethodsImmobility in the tail suspension test was used as an index of depression‐like behavior. NYT (1,000 or 2,000 mg/kg/day, once a day for seven days) was orally administered to mice. Prazosin and WAY‐100635 were administered 30 min and 1 h before the test, respectively. Norepinephrine (NE) and 5‐HT levels in the frontal cortex and amygdala were analyzed using a high‐performance liquid chromatography (HPLC) electrochemical detector.ResultsNYT (2000 mg/kg/day) shortened the immobility time. Prazosin and WAY‐100635 blocked the NYT‐mediated reduction in immobility time. NYT increased NE levels, but not 5‐HT levels, in the amygdala.ConclusionNYT reduced immobility time in the tail suspension test, likely by increasing NE levels. The increased NE levels may activate the α1‐adrenoceptor, thereby ameliorating the depression‐like behavior. NYT may therefore improve depressive symptoms in patients by enhancing the noradrenergic system.

Neurofilament light protein as a biomarker in depression and cognitive function.

Converging evidence suggest axonal damage is implicated in depression and cognitive function. Neurofilament light protein, measured within serum and cerebrospinal fluid, may be a biomarker of axonal damage. This article examines the emerging evidence implicating neurofilament light protein in depression and cognitive function. Preliminary cross-sectional and case-control studies in cohorts with depression have yielded inconsistent results regarding the association between neurofilament light protein and symptomatology. However, these studies had methodological limitations, requiring further investigation. Importantly, neurofilament light protein concentrations may be a marker of progression of cognitive decline and may be associated with cognitive performance within cognitively intact cohorts. Axonal damage is implicated in the neuropathology of depression and cognitive dysfunction. Consequently, neurofilament light protein is an emerging biomarker with potential in depression and cognitive function. Results are more consistent for cognition, requiring more research to assess neurofilament light protein in depression as well as other psychiatric disorders. Future longitudinal studies are necessary to determine whether neurofilament light protein can predict the onset and progression of depression and measure the effectiveness of potential psychiatric interventions and medications.

Cerebellar-cerebral dynamic functional connectivity alterations in major depressive disorder

BackgroundThe cerebellum plays an important role in the neural mechanism of depression and its static functional connectivity (FC) with the cerebrum is disrupted in patients with major depressive disorder (MDD). However, cerebellar-cerebral dynamic FC alterations in MDD remain largely unknown. Methods50 patients with MDD and 36 well-matched healthy controls underwent resting-state functional magnetic resonance imaging. Cerebellar-cerebral dynamic FC analyses were performed using the cerebellar seeds previously identified as being involved in the executive, default-mode, affective-limbic, and motor networks. Inter-group differences in the cerebellar dynamic FC and their associations with clinical and cognitive variables were examined. ResultsCompared to healthy controls, patients with MDD had decreased cerebellar-cerebral dynamic FC of the cerebellar subregions connecting with the executive, default-mode and affective-limbic networks. The dynamic FC of the cerebellar subregion connecting with the affective-limbic network was related to severity of depression and anxiety symptoms in MDD patients. The dynamic FC of the cerebellar subregions connecting with the default-mode and affective-limbic networks were related to sustained attention and prospective memory in controls, while the correlations were inverse or non-significant in patients. LimitationsThe fairly modest sample size and potential medication effect may increase the instability of the results. ConclusionsOur findings provide further evidence for the pivotal role of the cerebellum in the neuropathology of depression, pointing to potential targets of cerebellar-cerebral pathways for alternative intervention or monitoring therapeutic responses.

Exploring the potential role of sonic hedgehog cell signalling pathway in antidepressant effects of nicotine in chronic unpredictable mild stress rat model

Nicotine is the most common and highly addictive drug of abuse, associated with several life-threatening diseases and high mortality. Nicotine abuse is the concerted effort to feel reward and fight depression in depressed individuals. The underlying mechanism of nicotine is to activate the brain reward system in the central nervous system and provide an antidepressant effect. Antidepressants provide their therapeutic effect by stimulating hippocampal neurogenesis, which can be correlated with brain derived neurotrophic factor (BDNF) expression in the hippocampus. BDNF interacts with Wnt/β-catenin and sonic hedgehog (Shh) signalling cascade to stimulate hippocampal neurogenesis. Shh is the marker of hippocampal neurogenesis and also involved in the neuropathology of depression. But knowledge in this area to identify the potential therapeutic target is limited. In our study, we explored the role of BDNF, Wnt/β-catenin and Shh signalling in depression and the involvement of these signalling pathways in providing an antidepressant effect by nicotine. Our investigations showed that chronic unpredictable mild stress induced depression results declined expression of BDNF, Wnt/β-catenin, Shh and its downstream transcription factors GLI1/2/3 and NKX2.2 in the hippocampus of male Wistar rat. Moreover, we also observed that nicotine administration increased the expression of these signalling molecules in providing the antidepressant effects.

Silymarin and silymarin nanoparticles guard against chronic unpredictable mild stress induced depressive-like behavior in mice: involvement of neurogenesis and NLRP3 inflammasome.

The neuropathology of depression is quite complex. Thus, treatment failures are frequent with current antidepressants, raising the need for more effective ones. This study aimed to investigate the influence of silymarin on depressive-like behavior induced by chronic unpredictable mild stress (CUMS) and explore the underlying mechanisms. Silymarin was formulated as nanostructured lipid carriers (a lipid-based type of nanoparticle with the advantages of physical stability, good release profile, and targeted delivery). Mice were subjected to CUMS paradigm during 14 days. During this period, mice received silymarin (200 mg/kg, p.o.) per se or in its nanoparticle form or fluoxetine (10 mg/kg, p.o.). On the 15th day behavioral and biochemical parameters were analyzed. Oral administration of silymarin (200 mg/kg), particularly in its nanoparticulate form, exerted an antidepressant-like effect, comparable with fluoxetine in mice, as demonstrated in the behavioral despair tests. Silymarin also reversed prefrontal cortical and hippocampal CUMS-induced oxidative stress and neuroinflammation. Furthermore, silymarin augmented neurotransmitter levels, enhanced neurogenesis and inhibited nod-like receptor protein 3 inflammasome activation. Silymarin nanoparticles were superior to silymarin in certain parameters probably due to significantly higher brain silybinin (the major active component of silymarin) concentration by 12.46 fold in the group administered silymarin nanoparticles compared with the mice which were administered silymarin per se. The antidepressant-like effect of silymarin can be attributed to its antioxidant and anti-inflammatory effects as well as increased neurogenesis in the prefrontal cortex and hippocampus, which delineates silymarin, especially in nanoparticle form, as a promising strategy for treatment of depression.

Abnormal Functional Connectivity of Ventral Anterior Insula in Asthmatic Patients with Depression.

Objective To explore the underlying mechanism of depression in asthmatic patients, the ReHo in the insula and its FC was used to probe the differences between depressed asthmatic (DA) and nondepressed asthmatic (NDA) patients. Methods 18 DA patients, 24 NDA patients, and 60 healthy controls (HCs) received resting-state fMRI scan, severity of depression, and asthma control assessment. Results DA patients showed increased FC between the left ventral anterior insula (vAI) and the left middle temporal gyrus compared with both NDA and HC groups. In addition, compared with HCs, the DA and NDA patients both exhibited increased FC between the left vAI and the right anterior cingulate cortex (ACC), decreased FC between the left vAI and the bilateral parietal lobe, and increased FC between the right vAI and the left putamen and the right caudate, respectively. Furthermore, the increased FC between the left vAI and the right ACC could differentiate HCs from both DA and NDA patients, and the increased FC between the right vAI and both the left putamen and the right caudate could separate NDA patients from HCs. Conclusions This study confirmed that abnormal vAI FC may be involved in the neuropathology of depression in asthma. The increased FC between the left vAI and the left MTG could distinguish DA from the NDA and HC groups.

Dysfunction of the cingulo-opercular network in first-episode medication-naive patients with major depressive disorder

BackgroundMajor depressive disorder (MDD) is a common psychiatric disorder that may be associated with abnormal cognitive control and emotion regulation. Previous studies have found that network disconnection within the cingulo-opercular network (CON) plays an important role in psychiatric disorders and that the CON may be relevant to the psychopathology of MDD. We thus used the resting-state functional connectivity method in patients with MDD and healthy controls to examine CON neural circuit abnormalities in MDD. MethodsUsing resting-state functional magnetic resonance imaging (fMRI), we investigated the resting state functional connectivity of the CON using the dorsal anterior cingulate cortex (dACC) as the seed region of interest. The resulting functional connectivity (FC) correlation maps were employed to investigate between-group differences. Additionally, we examined the association between depression symptom severity and functional connectivity results. The participants were patients with MDD (n=19) and healthy controls (n=19). ResultsPatients with MDD showed abnormalities in the connectivity of the CON. We found abnormal connectivity in MDD patients between the dACC and the bilateral middle frontal gyrus (MFG) and left angular gyrus (LAG) and precentral gyrus. Moreover, regression analysis showed that depression symptom severity (measured with the Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale (HARS) and Automatic Thoughts Questionnaire scores (ATQ)) was significantly correlated with the FC values of the CON. LimitationsFirst, our study consisted of a relatively small sample size that may have limited statistical power. Second, the current study design cannot conclusively specify the role of the CON in the neuropathology of depression. ConclusionsOur findings suggest that MDD is associated with disrupted FC of the CON, which plays an important role in the pathophysiological mechanisms of MDD.

Individual Variations in Nucleus Accumbens Responses Associated with Major Depressive Disorder Symptoms.

Abnormal reward-related responses in the nucleus accumbens (NAcc) have been reported for major depressive disorder (MDD) patients. However, variability exists in the reported results, which could be due to heterogeneity in neuropathology of depression. To parse the heterogeneity of MDD we investigated variation of NAcc responses to gain and loss anticipations using fMRI. We found NAcc responses to monetary gain and loss were significantly variable across subjects in both MDD and healthy control (HC) groups. The variations were seen as a hyperactive response subtype that showed elevated activation to the anticipation of both gain and loss, an intermediate response with greater activation to gain than loss, and a suppressed-activity with reduced activation to both gain and loss compared to a non-monetary condition. While these response variability were seen in both MDD and HC subjects, specific symptoms were significantly associated with the right NAcc variation in MDD. Both the hyper- and suppressed-activity subtypes of MDD patients had severe suicidal ideation and anhedonia symptoms. The intermediate subjects had less severity in these symptoms. These results suggest that differing propensities in reward responsiveness in the NAcc may affect the development of specific symptoms in MDD.

Interhemispheric resting state functional connectivity abnormalities in unipolar depression and bipolar depression

Depression in the context of bipolar disorder (BD) is often misdiagnosed as unipolar depression (UD), leading to mistreatment and poor clinical outcomes. However, little is known about the similarities and differences in interhemispheric functional connectivity between BD and UD. Patients with bipolar II disorder (n=36) and UD (n=32) during a depressive episode as well as 40 healthy controls underwent resting-state functional magnetic resonance imaging. The functional connectivity between any pair of symmetric interhemispheric voxels (i.e., functional homotopy) was measured by voxel-mirrored homotopic connectivity (VMHC). The three groups showed significant VMHC differences in the posterior cingulate cortex (PCC), fusiform and lingual gyrus, anterior lobe of the cerebellum (CeAL), and posterior lobe of the cerebellum (CePL). In the BD group, the VMHC decreases in the fusiform/lingual gyrus, CeAL, and CePL were shown relative to controls. In the UD group, the VMHC decreases in the PCC, fusiform/lingual gyrus, and CePL were shown relative to controls. No regions of increased VMHC were detected in either patient group. There was no significant difference in the VMHC values in any brain region between the BD group and the UD group. Depressive episodes in BD and UD have similar impairments of interhemispheric coordination, which might imply an overlap in the neuropathology of depression.

Minocycline treatment ameliorates interferon-alpha- induced neurogenic defects and depression-like behaviors in mice.

Interferon-alpha (IFN-α) is a proinflammatory cytokine that is widely used for the treatment of chronic viral hepatitis and malignancy, because of its immune-activating, antiviral, and antiproliferative properties. However, long-term IFN-α treatment frequently causes depression, which limits its clinical utility. The precise molecular and cellular mechanisms of IFN-α-induced depression are not currently understood. Neural stem cells (NSCs) in the hippocampus continuously generate new neurons, and some evidence suggests that decreased neurogenesis plays a role in the neuropathology of depression. We previously reported that IFN-α treatment suppressed hippocampal neurogenesis and induced depression-like behaviors via its receptors in the brain in adult mice. However, it is unclear how systemic IFN-α administration induces IFN-α signaling in the hippocampus. In this study, we analyzed the role of microglia, immune cells in the brain, in mediating the IFN-α-induced neurogenic defects and depressive behaviors. In vitro studies demonstrated that IFN-α treatment induced the secretion of endogenous IFN-α from microglia, which suppressed NSC proliferation. In vivo treatment of adult mice with IFN-α for 5 weeks increased the production of proinflammatory cytokines, including IFN-α, and reduced neurogenesis in the hippocampus. Both effects were prevented by simultaneous treatment with minocycline, an inhibitor of microglial activation. Furthermore, minocycline treatment significantly suppressed IFN-α-induced depressive behaviors in mice. These results suggest that microglial activation plays a critical role in the development of IFN-α-induced depression, and that minocycline is a promising drug for the treatment of IFN-α-induced depression in patients, especially those who are low responders to conventional antidepressant treatments.

Neuropathology of depression in Alzheimer's disease: current knowledge and the potential for new treatments.

Depression is among the most common behavioral and psychological symptoms of dementia, and leads to more rapid decline and higher mortality. Treatment for depression in dementia has centered on conventional antidepressant drug treatment based around the monoamine hypothesis of depression. However, recent major studies have suggested that conventional antidepressant treatments that aim to correct underlying deficits in monoamine neurotransmitters are not effective for depression in dementia. Postmortem studies have also suggested that depression in dementia does not arise from serotonergic or noradrenergic abnormalities, or indeed from the degenerative pathology associated with Alzheimer's disease. In contrast, considerable recent evidence has suggested that alterations in glutamatergic transmission may contribute to the pathophysiology of depression. This supports the view that treatment-resistant depressed patients, such as many dementia patients, may benefit from agents affecting glutamate transmission. This review will thus draw together the wealth of pathological data examining the basis of depression in Alzheimer's disease and relate this to current thinking on treatment, with the aim of generating discussion on potential novel therapeutic strategies.

Similarities of biochemical abnormalities between major depressive disorder and bipolar depression: A proton magnetic resonance spectroscopy study

BackgroundDepression in the context of bipolar disorder (BD) is often misdiagnosed as major depressive disorder (MDD), leading to mistreatments and poor clinical outcomes for many bipolar patients. Previous neuroimaging studies found mixed results on brain structure, and biochemical metabolism of the two disorders. To eliminate the compounding effects of medication, and aging, this study sought to investigate the brain biochemical changes of treatment-naïve, non-late-life patients with MDD and BD in white matter in prefrontal (WMP) lobe, anterior cingulate cortex (ACC) and hippocampus by using proton magnetic resonance spectroscopy (1H-MRS). MethodsThree groups of participants were recruited: 26 MDD patients, 20 depressed BD patients, and 13 healthy controls. The multi-voxel 1H-MRS [repetition time (TR)=1000ms; echo-time (TE)=144ms] was used for the measurement of N-acetylaspartate(NAA), choline containg compounds (Cho), and creatine (Cr) in three brain locations: white matter in prefrontal (WMP) lobe, anterior cingulate cortex (ACC), and hippocampus. Two ratios of NAA/Cr and Cho/Cr as a measure of brain biochemical changes were compared among three experimental groups. ResultsOn the comparison of brain biochemical changes, both MDD patients and BD patients showed many similarities compared to the controls. They both had a significantly lower NAA/Cr ratio in the left WMP lobe. There were no significant differences among three experimental groups for Cho/Cr ratio in the WMP lobe, and for the ratios of NAA/Cr and Cho/Cr in the bilateral ACC and hippocampus. The only difference between MDD and BD patients existed for the NAA/Cr ratio in the right WMP lobe. While MDD patients had a significantly lower NAA/Cr ratio than controls, BD patients showed no such differences. On the comparison of correlation of medical variables and brain biochemical changes, all participants demonstrated no significant correlations. ConclusionReduced NAA/Cr ratio at the left WMP lobe indicated the dysfunction of neuronal viability in deep white matter, in both MDD and BD patients who shared similarities of brain biochemical abnormalities, which might imply an overlap in neuropathology of depression.

Classical hallucinogens as antidepressants? A review of pharmacodynamics and putative clinical roles.

Hallucinogens have been part of spiritual practice for millennia, but controversy surrounding their mind-manifesting effects led to their proscription by the mid-20th century, largely without evidence of harm or toxicity and despite nascent data suggesting therapeutic utility in treating depressive illnesses. This review explores their pharmacodynamic actions and the current limited data on their clinic effectiveness. These drugs appear to exert their psychedelic effects through their agonist or partial agonist activity at the serotonergic 5-HT2A receptor, though they also have affinity for other metabotropic serotonin receptors. Hallucinogen binding affects a wide range of intracellular signalling pathways, the precise nature of which remains incompletely understood. They alter the serotonergic tone of brainstem raphe nuclei that project through the brain; they interact with receptors in the prefrontal cortex altering connectivity patterns and intracellular functioning; and they disrupt inhibitory control of sensory input via the thalamus to the cortex. The serotonergic system has long been implicated in anxiety and depressive disorders, and is a major target of most existing antidepressants. Classical hallucinogens alter the functioning of this system, but not in the same way current medications do: whilst there are identified receptors and neurotransmitter pathways through which hallucinogens could therein produce therapeutic effects, the neurobiology of this remains speculative at this time. There is currently an extremely limited but growing literature on hallucinogen safety and clinical application. The drugs appear well tolerated by healthy controls and clinical populations, and the rapid tolerance to repeated administration might reduce the possibility of dependency. Clinical trials reported over the past decade have generally shown positive therapeutic potential, but they are notably few in number. Legislative policy has had a freezing effect on evaluation of these compounds, a better understanding of which might improve our knowledge of the processes involved in consciousness, the neuropathology of depression, and potentially open up new pharmacological therapies.

Analysis of oxysterols and cholesterol in prefrontal cortex of suicides

Brain oxysterol levels, which are enzymatic oxidation products of cholesterol (Chl), have been proposed to reflect the dynamic process of physiological synapse maintenance and repair of nerve terminals within the central nervous system (CNS), due to the turnover of membrane Chl. Modifications of oxysterols have important implications in neurological conditions, especially in neurodegenerative and psychiatric disorders in which alterations of synaptic plasticity or cell signalling are implicated, such as depression. Oxysterols can diffuse across the blood-brain barrier and have been hypothesized to provide a mechanism by which the brain can eliminate excess Chl to maintain a steady state. Relations of 24-hydroxycholesterol (24OH) and 27-hydroxycholesterol (27OH) specifically may provide a depiction of CNS Chl homeostasis. Thus, the objective of this study was to integrate oxysterol measures and gene expression measures in an effort to identify how they may relate to depression and suicide. Using post-mortem human prefrontal cortex tissue, quantification of metabolites by GC-MS and gene expression by qRT-PCR were performed with the aim to provide a characterization of enzymatic oxidative Chl homeostasis. Results show a significant increase in 24OH, which suggests a higher turnover of Chl to 24OH in the prefrontal cortex of suicide cases. An increase in 24OH may, in combination with liver-X receptor activation, explain the observed reduction of low central and peripheral Chl in suicide and would have implications for synapse maintenance and loss in the neuropathology of depression and suicide.