Systematic review of structured care pathways in major depressive disorder and bipolar disorder.

BACKGROUND: Structured care pathways (SCPs) consist of treatment algorithms that patients advance through with the goal of achieving remission or response. These SCPs facilitate the application of current evidence and adequate treatment, which potentially benefit patients with mood disorders. The aim of this systematic review was to provide an updated synthesis of SCPs for the treatment of depressive disorders and bipolar disorder (BD). METHOD: PubMed, PsycINFO, and Embase were searched through June 2022 for peer-reviewed studies examining outcomes of SCPs. Eligibility criteria included being published in a peer-reviewed journal in the English language, reporting of intervention used in the SCP, and having quantitative outcomes. Studies Cochrane risk of bias tool was used to assess quality of RCTs. RESULTS: Thirty-six studies including 15,032 patients were identified for qualitative synthesis. Six studies included patients with BD. The studies were highly heterogeneous in design, outcome measures, and algorithms. More than half of the studies reported superiority of SCPs over treatment as usual, suggesting that the standardized structure and consistent monitoring inherent in SCPs may be contributing to their effectiveness. We also found accumulating evidence supporting feasibility of SCPs in different settings, although dropout rates were generally higher in SCPs. The studies included were limited to being published in peer-reviewed journals in English language. The heterogeneity of studies did not allow quantitative evaluation. CONCLUSIONS: The findings of our study suggest that SCPs are equally or more effective than treatment as usual in depression and BD. Further studies are required to ascertain their effectiveness, particularly for BD, and to identify factors that influence their feasibility and success.

Venlafaxine XR treatment for older patients with major depressive disorder: decision trees for when to change treatment.

BACKGROUND: Predictors of antidepressant response in older patients with major depressive disorder (MDD) need to be confirmed before they can guide treatment. OBJECTIVE: To create decision trees for early identification of older patients with MDD who are unlikely to respond to 12 weeks of antidepressant treatment, we analysed data from 454 older participants treated with venlafaxine XR (150-300 mg/day) for up to 12 weeks in the Incomplete Response in Late-Life Depression: Getting to Remission study. METHODS: We selected the earliest decision point when we could detect participants who had not yet responded (defined as >50% symptom improvement) but would do so after 12 weeks of treatment. Using receiver operating characteristic models, we created two decision trees to minimise either false identification of future responders (false positives) or false identification of future non-responders (false negatives). These decision trees integrated baseline characteristics and treatment response at the early decision point as predictors. FINDING: We selected week 4 as the optimal early decision point. Both decision trees shared minimal symptom reduction at week 4, longer episode duration and not having responded to an antidepressant previously as predictors of non-response. Test negative predictive values of the leftmost terminal node of the two trees were 77.4% and 76.6%, respectively. CONCLUSION: Our decision trees have the potential to guide treatment in older patients with MDD but they require to be validated in other larger samples. CLINICAL IMPLICATIONS: Once confirmed, our findings may be used to guide changes in antidepressant treatment in older patients with poor early response.

Changes in RNA expression levels during antidepressant treatment: a systematic review.

More than a third of patients treated with antidepressants experience treatment resistance. Furthermore, molecular pathways involved in antidepressant effect have yet to be fully understood. Therefore, we performed a systematic review of clinical studies that examined changes in RNA expression levels produced by antidepressant treatment. Literature search was performed through April 2021 for peer-reviewed studies measuring changes in mRNA or non-coding RNA levels before and after antidepressant treatment in human participants following PRISMA guidelines. Thirty-one studies were included in qualitative synthesis. We identified a large amount of heterogeneity between the studies for genes/RNAs measured, antidepressants used, and treatment duration. Of the six RNAs examined by more than one study, expression of the brain-derived neurotrophic factor (BDNF) gene and genes in the inflammation pathway, particularly IL-1ß, were consistently reported to be altered by antidepressant treatment. Limitations of this review include heterogeneity of the studies, possibility of positive publication bias, and risk of false-negative findings secondary to small sample sizes. In conclusion, our systematic review provides an updated synthesis of RNA expression changes produced by antidepressant treatment in human participants, where genes in the BDNF and inflammatory pathways were identified as potential targets of antidepressant effect. Importantly, these findings also highlight the need for replication of the included studies in multiple strong, placebo-controlled studies for the identification of evidence-based markers that can be targeted to improve treatment outcomes.

Plasma microRNA expression levels and their targeted pathways in patients with major depressive disorder who are responsive to duloxetine treatment.

Major depressive disorder (MDD) is a complex disorder with many pathways known to contribute to its pathogenesis, such as apoptotic signaling, with antidepressants having been shown to target these pathways. In this study, we explored microRNAs as predictive markers of drug response to duloxetine, a serotonin-norepinephrine reuptake inhibiter, using peripheral blood samples from 3 independent clinical trials (NCT00635219; NCT0059991; NCT01140906) comparing 6-8 weeks of treatment with duloxetine to placebo treatment in patients with MDD. Plasma microRNA was extracted and sequenced using the Ion Proton Sequencer. Rank feature selection analysis was used to identify microRNAs in the top 10th percentile for their differentiating ability between patients who remitted and did not remit with duloxetine treatment. The results were then compared between the 3 trials to see their replicability. To further validate our findings, we reasoned that the pathways targeted by these microRNAs would be those shown to be altered in MDD in pathway enrichment analysis. Hsa-miR-23a-3p, hsa-miR-16-5p, hsa-miR-146a-5p and hsa-miR-21-5p were identified in 2 or more trials as being able to differentiate patients who would remit with duloxetine treatment using samples collected before treatment initiation, suggesting that they may be good candidates for identification of predictive biomarkers of duloxetine response. Pathway enrichment analysis further showed that microRNAs identified as differentiating for duloxetine response target the apoptosis signaling pathway. Future studies examining these microRNAs outside of a clinical trial setting and exploring their role in MDD may further our understanding of MDD and antidepressant response.

Low brain-derived neurotrophic factor levels in post-mortem brains of older adults with depression and dementia in a large clinicopathological sample.

BACKGROUND: Disturbances in peripheral brain-derived neurotrophic factor (BDNF) have been reported in major depressive disorder (MDD). However, there are no studies measuring BDNF levels directly in post-mortem brains of older subjects with MDD and dementia. We aimed to verify if brain BDNF levels were lower in older adults with lifetime history of MDD with and without dementia. METHODS: BDNF levels of post-mortem brains from 80 community-dwelling older individuals with lifetime MDD with and without dementia were compared with levels from 80 controls without lifetime MDD. Participants with no reliable close informant, or with prolonged agonal state were excluded. Lifetime MDD was defined as at least one previous episode according to the Structured Clinical Interview for DSM (SCID). RESULTS: BDNF levels were lower in the MDD group with dementia than in participants with dementia and without MDD as confirmed by multivariate analysis adjusted for clinical and cardiovascular risk factors (ß = -0.106, 95%CI = -0.204; -0.009, p = 0.034). No difference was found in the group with MDD without dementia compared with their controls. LIMITATIONS: The retrospective assessment of a lifetime history of depression may be subject to information bias and this study only establishes a cross-sectional association between lifetime history of MDD and lower levels of BDNF in patients with dementia. CONCLUSIONS: In this community sample of older individuals, lower brain BDNF levels were found in cases with both lifetime MDD and dementia. Low BDNF levels could be a moderator to accelerated brain aging observed in MDD with dementia.

Examining redox modulation pathways in the post-mortem frontal cortex in patients with bipolar disorder through data mining of microRNA expression datasets.

The etiology of redox (reduction and oxidation) alterations in bipolar disorder (BD) is largely unknown. To explore whether microRNAs targeting redox enzymes may have a role in BD, we examined 3 frontal cortex microRNA expression datasets (Perkins [2007], Vladimirov [2009], and Miller [2009]; N for BD = 30-36 per dataset, N for controls = 28-34 per dataset) from the Stanley Neuropathology Consortium. Each dataset was analyzed separately because they were generated using different high-throughput platforms. Following the selection of only redox modulator-targeting microRNAs, microRNAs in the top 10th percentile in feature selection could together discriminate BD and controls at a greater frequency than expected by chance in classification analysis. In pathway enrichment analysis of all three datasets, these classifying microRNAs targeted the cellular nitrogen compound metabolic process pathway, which includes redox enzymes of the mitochondrial electron transport chain and the glutathione system. To see if this pathway would still emerge as significant if all microRNAs (not just redox-targeting) were analyzed, all analyses were repeated with the complete set of microRNAs. Cellular nitrogen compound metabolic process pathway was enriched in all 3 datasets in this analysis as well, demonstrating that preselection of redox microRNAs was not a requirement to identify this pathway for the discrimination of BD and controls. While preliminary, our findings suggest that microRNAs that target redox enzymes in this pathway may be good candidates for the exploration of causative factors contributing to redox alterations in BD. Future studies validating these findings in a separate set of central and peripheral samples are warranted.

Factors associated with brain volume in major depression in older adults without dementia: results from a large autopsy study.

OBJECTIVE: We examined brain volume and atrophy in individuals with major depressive disorder (MDD) without dementia that were referred to a large autopsy service. We also examined potential risk factors for brain atrophy, including demographics and clinical variables. METHODS: In this study, 1373 participants (787 male) aged 50 years or older who died from natural causes were included. Participants with no reliable informant, with cognitive impairment or dementia, with a medical history of severe chronic disease, or with prolonged agonal state were excluded. Presence of MDD at least once in their lifetime was defined according to the Structured Clinical Interview for DSM. Brain volume was measured immediately after removal from the skull. RESULTS: Mean age at death was 68.6 ± 11.6, and MDD was present in 185 (14%) individuals. Smaller brain volume was associated with older age (p < 0.001), lower education (years; p < 0.001), hypertension (p = 0.001), diabetes (p = 0.006), and female gender (p < 0.001). In the multivariate analysis adjusted for sociodemographics and cardiovascular risk factors, smaller brain volume was not associated with major depression (ß = -0.86, 95% CI = -26.50 to 24.77, p = 0.95). CONCLUSIONS: In this large autopsy study of older adults, MDD was not associated with smaller brain volumes. Regardless of the presence of MDD, in this sample of older adults without dementia, we found that smaller brain volumes were associated with risk factors for brain neurodegeneration such as older age, diabetes, hypertension, and lower education. Copyright © 2017 John Wiley & Sons, Ltd.

Neuropathological relationship between major depression and dementia: A hypothetical model and review.

Major depression (MDD) is a chronic psychiatric condition in which patients often show increasing cognitive impairment with recurring episodes. Neurodegeneration may play an important component in the pathogenesis of MDD associated with cognitive complaints. In agreement with this, patients with MDD show decreased brain volumes in areas implicated in emotional regulation and cognition, neuronal and glial cell death as well as activation of various pathways that can contribute to cell death. Therefore, the aim of this review is to provide an integrative overview of potential contributing factors to neurodegeneration in MDD. Studies have reported increased neuronal and glial cell death in the frontal cortex, amygdala, and hippocampus of patients with MDD. This may be due to decreased neurogenesis from lower levels of brain-derived neurotrophic factor (BDNF), excitotoxicity from increased glutamate signaling, and lower levels of gamma-aminobutyric acid (GABA) signaling. In addition, mitochondrial dysfunction and oxidative stress are found in similar brain areas where evidence of excitotoxicity has been reported. Also, levels of antioxidant enzymes were reported to be increased in patients with MDD. Inflammation may also be a contributing factor, as levels of inflammatory cytokines were reported to be increased in the prefrontal cortex of patients with MDD. While preliminary, studies have also reported neuropathological alterations in patients with MDD. Together, these studies suggest that lower BDNF levels, mitochondrial dysfunction, oxidative stress, inflammation and excitotoxicity may be contributing to neuronal and glial cell death in MDD, leading to decreased brain volume and cognitive dysfunction with multiple recurrent episodes. This highlights the need to identify specific pathways involved in neurodegeneration in MDD, which may elucidate targets that can be treated to ameliorate the effects of disease progression in this disorder.

Nod-like receptor pyrin containing 3 (NLRP3) in the post-mortem frontal cortex from patients with bipolar disorder: A potential mediator between mitochondria and immune-activation.

Mitochondrial complex I dysfunction, oxidative stress and immune-activation are consistently reported in bipolar disorder (BD). Mitochondrial production of reactive oxygen species was recently linked to activation of an inflammatory redox sensor, the nod-like receptor family pyrin domain-containing 3 (NLRP3). Upon its activation, NLRP3 recruits apoptosis-associated speck-like protein (ASC) and caspase-1 to form the NLRP3-inflammasome, activating IL-1ß. This study aimed to examine if immune-activation may be a downstream target of complex I dysfunction through the NLRP3-inflammasome in BD. Post-mortem frontal cortex from patients with BD (N = 9), schizophrenia (N = 10), and non-psychiatric controls (N = 9) were donated from the Harvard Brain Tissue Resource Center. Levels of NLRP3, ASC and caspase-1 were measured by western blotting, ELISA and Luminex. While we found no effects of age, sex or post-mortem delay, lower levels of complex I (F2,25 = 3.46, p < 0.05) and NDUFS7, a subunit of complex I (F2,25 = 4.13, p < 0.05), were found in patients with BD. Mitochondrial NLRP3 (F2,25 = 3.86, p < 0.05) and ASC (F2,25 = 4.61, p < 0.05) levels were higher in patients with BD. However, levels of caspase 1 (F2,25 = 4.13, p < 0.05 for both), IL-1ß (F2,25 = 7.05, p < 0.01), IL-6 (F2,25 = 5.48, p < 0.05), TNFα (F2,25 = 7.14, p < 0.01) and IL-10 (F2,25 = 5.02, p < 0.05) were increased in both BD and schizophrenia. These findings suggest that immune-activation in the frontal cortex may occur both in patients with BD and schizophrenia, while complex I dysfunction and NLRP3-inflammasome activation may be more specific to BD.

The Potential Role of the NLRP3 Inflammasome as a Link between Mitochondrial Complex I Dysfunction and Inflammation in Bipolar Disorder.

Mitochondrial dysfunction and activation of the inflammatory system are two of the most consistently reported findings in bipolar disorder (BD). More specifically, altered levels of inflammatory cytokines and decreased levels of mitochondrial complex I subunits have been found in the brain and periphery of patients with BD, which could lead to increased production of mitochondrial reactive oxygen species (ROS). Recent studies have shown that mitochondrial production of ROS and inflammation may be closely linked through a redox sensor known as nod-like receptor pyrin domain-containing 3 (NLRP3). Upon sensing mitochondrial release of ROS, NLRP3 assembles the NLRP3 inflammasome, which releases caspase 1 to begin the inflammatory cascade. In this review, we discuss the potential role of the NLRP3 inflammasome as a link between complex I dysfunction and inflammation in BD and its therapeutic implications.

Glutathione-mediated effects of lithium in decreasing protein oxidation induced by mitochondrial complex I dysfunction.

The aim of this study was to elucidate whether glutathione is involved in lithium's ability to decrease carbonylation and nitration produced by complex I inhibition, which is consistently found in BD. Neuroblastoma cells were treated with rotenone, a complex I inhibitor. Our results suggest that glutathione is essential for lithium's ability to ameliorate rotenone-induced protein carbonylation, but not nitration.

Vitis labrusca extract effects on cellular dynamics and redox modulations in a SH-SY5Y neuronal cell model: a similar role to lithium.

Oxidative stress and calcium imbalance are consistently reported in bipolar disorder (BD). Polymorphism of voltage-dependent calcium channel, L type, alpha 1C subunit (CACNA1c), which is responsible for the regulation of calcium influx, was also shown to have a strong association with BD. These alterations can lead to a number of different consequences in the cell including production of reactive species causing oxidative damage to proteins, lipids and DNA. Lithium is the most frequent medication used for the treatment of BD. Despite lithium's effects, long-term use can result in many negative side effects. Therefore, there is an urgent need for the development of drugs that may have similar biological effects as lithium without the negative consequences. Moreover, polyphenols are secondary metabolites of plants that present multi-faceted molecular abilities, such as regulation of cellular responses. Vitis labrusca extract (VLE), a complex mixture of polyphenols obtained from seeds of winery wastes of V. labrusca, was previously characterized by our group. This extract presented powerful antioxidant and neuroprotective properties. Therefore, the ability of VLE to ameliorate the consequences of hydrogen peroxide (H2O2)-induced redox alterations to cell viability, intracellular calcium levels and the relative levels of the calcium channel CACNA1c in comparison to lithium's effects were evaluated using a neuroblastoma cell model. H2O2 treatment increased cell mortality through apoptotic and necrotic pathways leading to an increase in intracellular calcium levels and alterations to relative CACNA1c levels. VLE and lithium were found to similarly ameliorate cell mortality through regulation of the apoptotic/necrotic pathways, decreasing intracellular calcium levels and preventing alterations to the relative levels of CACNA1c. The findings of this study suggest that VLE exhibits protective properties against oxidative stress-induced alterations similar to that of lithium. These findings suggest that VLE may be an attractive potential candidate as a novel therapeutic agent for BD.

Oxidation and nitration in dopaminergic areas of the prefrontal cortex from patients with bipolar disorder and schizophrenia.

BACKGROUND: Increased oxidative stress is strongly implicated in bipolar disorder (BD), where protein oxidation, lipid peroxidation and oxidative damage to DNA have been consistently reported. High levels of dopamine (DA) in mania are also well-recognized in patients with BD, and DA produces reactive oxygen species and electron-deficient quinones that can oxidize proteins when it is metabolized. METHODS: Using immunohistochemistry and acceptor photobleaching Förster resonance energy transfer (FRET), we examined oxidation and nitration of areas immunoreactive for the DA transporter (DAT) and tyrosine hydroxylase (TH) in the postmortem prefrontal cortex from patients with BD, schizophrenia and major depression as well as nonpsychiatric controls. RESULTS: We found increased oxidation of DAT-immunoreactive regions in patients with BD (F3,48 = 6.76, p = 0.001; Dunnett post hoc test p = 0.001) and decreased nitration of TH-immunoreactive regions in both patients with BD (F3,45 = 3.10, p = 0.036; Dunnett post hoc test p = 0.011) and schizophrenia (p = 0.027). On the other hand, we found increased global levels of oxidation in patients with BD (F3,44 = 6.74, p = 0.001; Dunnett post hoc test p = 0.001) and schizophrenia (p = 0.020), although nitration levels did not differ between the groups (F3,46 = 1.75; p = 0.17). LIMITATIONS: Limitations of this study include the use of postmortem brain sections, which may have been affected by factors such as postmortem interval and antemortem agonal states, although demographic factors and postmortem interval were accounted for in our statistical analysis. CONCLUSION: These findings suggest alterations in levels of protein oxidation and nitration in DA-rich regions of the prefrontal cortex in patients with BD and schizophrenia, but more markedly in those with BD.

The relationship between oxidative stress and post-translational modification of the dopamine transporter in bipolar disorder.

Bipolar disorder (BD) has been consistently associated with altered levels of oxidative stress markers, although the cause and consequences of these alterations remain to be elucidated. One of the main hypotheses regarding the pathogenesis of mania involves increased dopaminergic transmission. In this review, the authors aim to discuss a potential mechanism by which increased oxidative stress inhibits the uptake of dopamine through the post-translational modification of the dopamine transporter and its implications for BD. Within the next 5 years, the authors believe that the mechanisms of dopamine transporter oxidation and its impact on the pathophysiology of BD will be elucidated, which may open avenues for the development of more specific interventions for the treatment of this debilitating illness.